PDE10A Mutations Help to Unwrap the Neurobiology of Hyperkinetic Disorders T ⁎ Ellanor L

Cellular Signalling 60 (2019) 31–38

Contents lists available at ScienceDirect

Cellular Signalling

journal homepage: www.elsevier.com/locate/cellsig

Review PDE10A mutations help to unwrap the neurobiology of hyperkinetic disorders T ⁎ Ellanor L. Whiteleya, Gonzalo S. Tejedaa, George S. Bailliea, Nicholas J. Brandonb, a Institute of Cardiovascular and Medical Science, University of Glasgow, Glasgow G12 8QQ, UK b IMED Biotech Unit, R&D, AstraZeneca Neuroscience, Boston, MA 024515, USA

ARTICLE INFO ABSTRACT

Keywords: The dual-specific cAMP/cGMP phosphodiesterase PDE10A is exclusively localised to regions of the brain and PDE10A specific cell types that control crucial brain circuits and behaviours. The downside to this expression pattern is Hyperkinetic movement disorders that PDE10A is also positioned to be a key player in pathology when its function is perturbed. The last decade of Striatum research has seen a clear role emerge for PDE10A inhibition in modifying behaviours in animal models of GAF domain psychosis and Huntington's disease. Unfortunately, this has not translated to the human diseases as expected. cAMP More recently, a series of families with hyperkinetic movement disorders have been identified with mutations Huntington's disease altering the PDE10A protein sequence. As these mutations have been analysed and characterised in other model systems, we are beginning to learn more about PDE10A function and perhaps catch a glimpse into how PDE10A activity could be modified for therapeutic benefit.

1. Introduction The activation of these distinct pathways within the striatum rely on the tuning of the intracellular second messenger molecules, cyclic 3′ 5′- Hyperkinetic movement disorders are a heterogeneous group of adenosine monophosphate (cAMP) and cyclic 3′ 5′-guanosine mono- clinical diagnoses, defined as uncontrolled excess movement that phosphate (cGMP). cAMP is generated in response to extracellular cues manifests in a number of ways, including but not limited to tremor, to orchestrate numerous physiological processes by activation of a dystonia, tics and chorea, which for the context of this PDE10A review range of effector proteins [12]. Production of this cyclic nucleotide is is best exemplified by Huntington's Disease (HD) [1,2]. They are as well exemplified in the dopamine system, with binding of dopamine to frequent as hypokinetic movement disorders, best illustrated by Par- the D1R resulting in activation of the coupled stimulatory Gαs protein, kinson's Disease (PD). The basal ganglia are a group of subcortical which in turn activates adenylyl cyclases (ACs) and triggers cAMP nuclei primarily responsible for the selection and synchronisation of synthesis and neuronal excitability through modulation of cAMP ef- movement cues from cortical outputs, but which also influence moti- fector protein activity. In contrast, ligand binding to D2Rs results in vation and cognitive behaviour [3,4]. The striatum is the main input inactivation of ACs through release of the inhibitory Gαi protein and region of the basal ganglia and is comprised of principally GABAergic suppresses membrane depolarisation [13]. In light of these opposing medium spiny neurons (MSNs), the main neuronal cell type lost in HD, forces, orchestration of the temporal/spatial synthesis and degradation and cholinergic interneurons [5,6]. MSNs can be classified into two of cAMP is crucial to illicit the appropriate receptor-speci fic physiolo- distinct groups based on the destination of their axonal projections and gical effect. cGMP is generated by guanylyl cyclases (GCs), which in the molecular expression patterns, especially the G-protein coupled re- brain can be membrane-bound particulate GC or soluble GC, and are ceptors (GPCRs) responsible for relaying the dopamine signal [7–9]. In activated by a number of different extracellular ligands or nitric oxide particular, the MSNs of the so-called ‘direct’ or ‘striatonigral’ pathway, respectively [14,15]. Shaping of cAMP and cGMP gradients in three which promote movement and express the dopamine D1 receptor dimensions occurs via the action of cyclic nucleotide phosphodies- (D1R), project to the substantia nigra and the internal globus pallidus. terases (PDEs) that degrade cAMP and/or cGMP by hydrolysing the 3′ While the ‘indirect’ or ‘striatopallidal’ pathway MSNs, which express cyclic phosphodiester bond to produce inactive 5’-AMP and 5’-GMP the dopamine D2 receptor (D2R) and inhibit movement, project to the respectively. To date there have been 11 PDE families described, yet it pallidum [10,11]. is believed over 100 mRNA products exist through alternative splicing

⁎ Corresponding author. E-mail address: [email protected] (N.J. Brandon). https://doi.org/10.1016/j.cellsig.2019.04.001 Received 11 February 2019; Received in revised form 31 March 2019; Accepted 1 April 2019 Available online 02 April 2019 0898-6568/ © 2019 Published by Elsevier Inc. E.L. Whiteley, et al. Cellular Signalling 60 (2019) 31–38

and transcriptional initiation sites [16,17]. PDE families can either has only been found at very high levels of cGMP, with an IC50 of 14 μM specifically hydrolyse cAMP, cGMP or possess dual specificity to hy- [39]. This suggests a preference of the catalytic domain for cAMP when drolyse both substrates. The functions of specific PDEs are uniquely cAMP is bound to the GAF-B domain, which is in agreement with influenced by their cellular localisation, often directed by targeting previous studies showing a higher affinity of PDE10A for cAMP [39,41]. sequences within the enzyme's N-terminal domain [18]. The identifi- In contrast, the GAF-A domain of PDE10A does not contain the typical cation of region-specific expression of different PDEs within the brain cyclic nucleotide binding consensus motif, N[KR]X(5–14)FX(3)DE or highlighted that an intricate crosstalk between families exists in order ‘NKFDE’, associated with cyclic nucleotide binding. Interestingly, not to strictly regulate cyclic nucleotide concentration, in a cell type spe- all GAF domains are found to bind cyclic nucleotides, and reports have cific manner which drives specific brain circuitry and subsequent be- also implicated GAF domains in protein-protein interactions, such as haviour [19–21]. Consequently, understanding of the various PDE the homodimerisation of PDE2 and PDE5 [45–48]. This infers another isoforms, their expression within different brain regions and the inter- means of regulation for PDE activity, through enzyme stability or play between one another is fundamental in the future development of subcellular localisation. The differential roles of the PDE10A GAF-A and therapeutics targeting PDEs in the CNS. -B domains will be discussed later in this review, as human mutations in Across PDE families, phosphodiesterase 10A (PDE10A) is almost the two domains have a distinct clinical presentation. exclusively detected in the brain, although it is also present in the testis As mentioned above, PDE localisation in cellular micro-domains [22,23] and overexpressed in several tumours [24–26]. In the brain, it often depends on targeting sequences within the N-terminal region and is enriched in the MSNs of the striatum, although reduced levels of the PDE10A is no different in this regard. Differential encoding of the ex- enzyme are also present in the cerebellum, hippocampus and cortex treme amino terminal regions account for distinct cellular localisation, [27]. PDE10A is expressed in both D1R-containing striatonigral and with PDE10A1 and PDE10A19 situated in the cytosol whereas D2R-containing striatopallidal MSNs [28–31]. The high expression of PDE10A2 is predominantly membrane-bound [32,33,40,43]. PDE10A2 PDE10A in the dendritic post-synaptic region helps PDE10A to or- is post-translationally and irreversibly palmitoylated at Cys11 in its chestrate incoming cortical glutaminergic and midbrain dopaminergic unique N-terminal region, facilitating its membrane association and signals, regulating MSN sensitivity [32–34] and critically influencing trafficking to dendrites (Figs. 1 and 2). Protein acyltransferases ZDHHC- various behaviours generated through engagement of downstream cir- 7 and ZDHHC-19, zinc-finger containing DHHC-containing proteins, we cuitry including movement and motivation. Simply through its dis- previously reported to mediate this palmitoylation [34]. Critically, tribution and implied function, somewhat mimicking a D2R antagonist, PDE10A2 contains an exclusive cAMP-dependent protein kinase (PKA) PDE10A inhibition has been considered as a therapeutic target for phosphorylation site at Thr16, which when phosphorylated interferes schizophrenia [35], and then more elegant human biology and brain with post-translational palmitoylation at Cys11 and prevents membrane circuitry studies have implicated this enzyme in movement disorders translocation of the enzyme (Figs. 1 and 2)[32,34]. Therefore, the in- such as HD and PD [36–38]. This review article will focus on the tracellular cAMP concentration at the time of protein synthesis tightly complicity of striatal PDE10A malfunction and the defective cyclic controls PDE10A2 localisation, and thus the compartmentalisation of nucleotide signalling in genetic hyperkinetic movement disorders. the cAMP gradient through PKA activation. Interestingly, over- expression of PDE10A19 has also been reported to interfere with 2. Structure, localisation and regulation of PDE10A within the membrane association of PDE10A2 through a direct interaction be- brain tween the isoforms [43]. Fine control of localised cyclic nucleotide gradients in neurons de- PDE10A is an 89 kDa dual-specific phosphodiesterase, able to hy- pends on the unique localisation of PDE10A2. Specifically, it has been drolyse both cAMP and cGMP with Km values 0.26 μM and 7.2 μM re- reported that PDE10A is a member of a signalling complex bound to spectively [39–41], although with a lower Vmax for cAMP compared synaptic membranes, including N-methyl-D-aspartate (NMDA) receptor with cGMP [41]. On a cellular level, PDE10A protein is present subunits and scaffolding proteins AKAP150 and PSD95 (Fig. 2). Phos- throughout the cell soma, dendrites and axons of MSNs with mRNA phorylation by PKA results in PDE10A2 dissociating from this complex expression largely confined to the cell body [27,42]. Outside the and diffusing horizontally through the plasma membrane [49]. There- striatum, brain regions such as the hippocampus, cerebellum, brainstem fore, when production of cAMP overrides the degradation capacity of and cortex, exhibited exclusive nuclear localisation of PDE10A [42]. PDE10A, the enzyme dissociates from the synaptic complex and allows Alternative splicing gives rise to over 30 transcripts in the human brain triggering of downstream signalling cascades. of which around half are human-specific, characterised by unique N- terminal and C-terminal regions [16,32,43]. Humans possess two pre- 3. PDE10A-related hyperkinetic movement disorders valent splice variants of PDE10A, PDE10A1 and the more abundant PDE10A2, whereas in rats PDE10A2 and PDE10A3 are more prominent Alterations in cyclic nucleotide levels have been extensively asso- (Kotera et al., 2004). A further primate-specific isoform, PDE10A19, ciated with HD, which results from a trinucleotide CAG repeat expan- has also more recently been described [16,43] and other variants are sion in the first exon of the huntingtin (htt) gene and is characterised by expected to be found as some novel PDE10A transcripts have been uncontrolled choreiform movements related to selective vulnerability predicted to express proteins with specific N-termini [16]. Conserved of MSNs. In early stage HD, degeneration of the inhibitory D2R-con- between the human variants are a carboxyl terminal catalytic region, taining striatopallidal MSNs is observed, in contrast to the seemingly and two regulatory GAF (cGMP-stimulated PDEs, Anabaena adenylyl more resilient D1R expressing cells [50]. D1R containing MSNs de- cyclases, and the Escherichia coli transcription factor FhlaA) domains generate as disease progresses, which results in hypokinetic movement (Fig. 1). GAF domains provide allosteric regulation sites on PDEs [44] consistent with the direct pathway becoming compromised [51]. Re- and are structurally different to cAMP binding sites of the PDE catalytic duced levels of cAMP have been measured in both post mortem brain domain and cAMP effector proteins. For the purpose of this review, the samples from HD patients and mouse models [52]. Interestingly, structure and function of the GAF domains are highly germane. PDE10A mRNA and protein levels are downregulated in HD patients PDE10A is unique in regard to its GAF domains, as it is the only PDE and animal models of HD prior to the onset of motor symptoms, with regulated by cAMP rather than cGMP [23]. Low concentrations of this reduction correlating to disease progression and severity cAMP (or a synthetic GAF domain agonist) stimulate degradation of [36,37,53–56]. Furthermore, the rate of transcriptional initiation of both cAMP and cGMP when bound to the GAF-B domain of PDE10A PDE10A was shown to be reduced in the striatum of R6/1 and R6/2 HD

(EC50 ∼ 0.1 μM), however the enzyme is completely inactivated at mice, indicating the possibility of PDE10A transcriptional repression by further elevated levels of cAMP [23]. Inhibition of cAMP degradation the mutant htt protein [37]. Conversely, PDE10A inhibitors have been

32 E.L. Whiteley, et al. Cellular Signalling 60 (2019) 31–38

Fig. 1. Schematic representation of human PDE10A isoforms. The three major PDE10A splice variants differ in their N-terminal amino acid sequence, which is responsible for the distinctive subcellular localisation pattern. Residues implicated in PDE10A2 trafficking to the plasma membrane are highlighted in bold: palmitoylated Cys11 that serves as an anchor for membrane insertion and phospho-residue Thr16 that can prevent palmitoylation. PDE10A functional domains, cyclic nucleotide binding consensus motif and mutations in PDE10A GAF domains that cause hyperkinetic movement disorders are indicated. Amino acid numbering refers to human PDE10A2. reported to rescue transcriptional, cellular and behavioural deficits in HD [63–67]. A total of five separate mutations in the PDE10A gene on HD mouse models [57,58]. If PDE10A levels are actively downregulated chromosome 6 have been reported in 14 individuals, with all mutations during the progression of HD, this raises the question as to why in- creating a single amino acid substitution in either the GAF-A or GAF-B hibition of PDE10A would be therapeutically beneficial. It has been domain of the protein (Table 1). Our own study [63] identified two hypothesised that PDE10A reduction is a compensatory mechanism to familial biallelic mutations within the GAF-A domain of PDE10A. The restore HD-related cyclic nucleotides decline, which should occur very first family was consanguineous and of Pakistani descent. Affected fa- early in the course of the disease. This happens via the activation of the mily members were shown to be homozygous for a c.320A > G muta- transcription factor cAMP-response element binding protein (CREB), tion causing a cysteine to replace a tyrosine at amino acid position 107 increased brain derived neurotrophic factor (BDNF) expression and in (p.Y107C). Clinical manifestations include axial hypotonia with dyski- turn, cell survival [59–61]. Such speculation was at least partially nesia of the face, trunk and limbs, however cognition was unimpaired. quashed by the results of a Phase II clinical trial led by Pfizer in HD with Notably, the degree of severity differed within the family, the oldest the PDE10A inhibitor PF-02545920 (ClinicalTrials.gov, member being least affected [63]. The second mutation (c.346G > C; NCT02197130). Unfortunately, PF-02545920 was shown to have no p.A116P) was identified in a Finnish family, who again presented with advantage versus placebo on the primary endpoint of the Unified- global dyskinesia and profound axial hypotonia. Cognitive impairment Huntington's-Disease-Rating-Scale Total-Motor-Score (UHDRS-TMS) was greater compared to the p.Y107C mutation, with language and [62]. movement milestones significantly delayed. The youngest of the In addition to HD, a series of familial mutations have recently p.A116P family presented with a more severe movement disorder, focal emerged implicating PDE10A in child-onset non-progressive hyperki- epilepsy and was required to feed by a gastrostomy tube [63]. Inter- netic movement disorders, with symptoms reminiscent of early-stage estingly, patients with these mutations in the GAF-A domain presented

Fig. 2. Post-translational regulation and traﬃcking of PDE10A. PDE10A2 palmitoylation at Cys11 facil- itates its traﬃcking and insertion into the plasma membrane of MSNs where it associates with synaptic proteins such as PSD95, AKAP150 and NMDA receptor subunits. High local cAMP levels can increase PKA activation which results in the phosphorylation of PDE10A2 at Thr16 preventing the action of the palmitoyl acyltransferase (zDHHC). Phosphorylated PDE10A2 accumulates in the cytosol in line with the other two major isoforms PDE10A1 and PDE10A19.

33 E.L. Whiteley, et al. Cellular Signalling 60 (2019) 31–38

with normal MRI scans. We also made a knock-in mouse model of the p.Y107C mutation (p.Y97C in mice). Mice homozygous for the mutation displayed a range of motoric phenotypes compared to mice heterozygous for the mutation and wild-type. This included reduced loco- motor activity in an open-field, reduced motor coordination on a ro- tarod and also a modified gait. To understand why the mutation had these effects, we investigated PDE10A at the transcript and protein

cits in motor control. level. Our detailed analyses of the mouse showed a marked reduction in fi the levels of striatal PDE10A mRNA and protein. We strongly believe ND Mouse models De Reduced striatal PDE10A levels and function ND that the mutation has an impact on transcript production and/or stability and also causes more rapid turnover of produced protein. A functional consequence of the reduction was demonstrated as phosphorylated CREB was not increased upon PF-02545920 administration compared to wild-type animals, indicating a loss of PDE10A activity. We also characterised levels of the PDE10A p.Y107C protein and transcripts after over-expression in HEK293 cells and we again identified a decrease in both PDE10A protein and mRNA levels compared to ect ect ff ff PDE10A Reduced PDE10A levels and activity Reduced cAMP-stimulatory e Normal basal activity Reduced cAMP-stimulatory e wild-type PDE10A expression. Interestingly, in this same over- expression system the p.A116P was shown to be even less stable than p.Y107C which might be connected to the more severe clinical presentation of the p.A116P family [63]. Amazingly (but perhaps ‘pre- dictably’ considering the data in mice and HEK293 cells) we were also able to show a decrease in the levels of PDE10A by PET imaging in man, albeit a single subject who was old enough to participate in such a study. Using a PDE10A-specific radioligand, we demonstrated a 70% reduction in striatal PDE10A signal independent of total striatal volume loss [63]. Such elegant translation across species gives us some belief that elevation of PDE10A levels and/or PDE10A function in these fa- Reduced PDE10A levels inganglia. basal Normal brain MRI Normal brain MRIBilateral striatocortical atrophy Reduced PDE10A levels ND Normal brain MRI NDmilial hyperkinetic ND disorder syndromes might have a beneficial clinical effect. The directionality of PDE10A activity we suggest here is of course opposite to the hypothesis around PDE10A inhibition in HD. De novo mutations in the cAMP-binding GAF-B domain were also identified in four unrelated individuals of European origin [64,65,67]. Two of these patients were heterozygous for a c.898T > C mutation (p.F300L), with the other two carrying a c.1000T > C (p.F334L) heterozygous mutation. Additionally, two related individuals of Indian decent have also been identified with a c.1001T > G (p.F334C) substitution [66]. Patients exhibited childhood-onset, non-progressive trunk and limbs trunk and limbs. Development delay restlessness. Development delay chorea yet all met cognitive and developmental milestones. Unlike the GAF-A domain mutations, MRI scanning of affected individuals showed bilateral striatal hyperintensities [64–66]. Interestingly, the younger patient (11 years) with the p.F334L mutation showed restricted diffu-

Age at onset Clinical presentation PDE10A imaging Biochemical impact on sion and striatal swelling, indicative of an active disease state. Diurnal ﬂuctuations of chorea were reported with the p.F334L mutation, with symptoms most prominent within 2 h of awakening, gradual improve- ment throughout the day and complete absence at night [64]. Adult carriers of the p.F300L mutation conversely presented striatal atrophy and nigrostriatal degeneration comparable to that of HD patients, who exhibit signiﬁcant striatal volumetric loss throughout the disease cor- Inheritance/ Dominance (No. cases) Familial/ Recessive (1) ~6 year Paroxysmal dyskinesia Fronto-parietal cortical atrophyrelating ND to motor impairment ND [65,68]. Moreover, these patients also showed a reduction in striatal and globus pallidus PDE10A levels to- gether with substantia nigra dysfunction [67]. On a molecular level, these mutations are located within the deep binding pocket of the GAF- B domain, where cAMP is bound and activates the wild-type enzyme ected

ff [69]. cAMP has been shown to interact with the GAF-B domain tightly PDE10A domain GAF-B Familial/ Dominant (2) ~4 year Non-progressive chorea Bilateral striatal hyperintensities ND ND a GAF-A Familial/ Recessive (6) ~3 month Generalized dyskinesia of face, GAF-B De novo/ Dominant (2) ~4 year Non-progressive chorea Bilateral striatal hyperintensities Normal basal activity GAF-A Familial/ Recessive (2) ~4 month Generalized dyskinesia of face, GAF-B De novo/ Dominant (2) ~7 year Non-progressive chorea Reduced striatal PDE10A levels. N-terminal region/ PDEase PDEase Familial/ Recessive (2) ~7 month Chorea, hyperkinesia and motor and specifically, therefore affinity or recognition of cAMP as a mod- ulator is likely to be affected in these mutations [70]. Mencacci and colleagues reported that the p.F300L and p.F334L mutations did not affect the basal activity of the enzyme yet inhibited the cAMP-stimu-

Ile625Phe latory eﬀect for cGMP hydrolysis [65]. Therefore, it is reasonable to ﬀ Phe334Cys Phe334Leu Leu675Pro assume that the symptomatic e ects of these GAF-B mutations may Tyr107Cys Glu67Gln Ala116Pro Phe300Leu interfere with the strict cAMP-dependent regulation of cyclic nucleotide hydrolysis. At this moment there are no comparisons of ‘GAF-A’ versus ‘GAF-B’ mutations across any model systems. These studies need to be c.1873A > T; p. conducted to understand how the two classes of mutation drive disease c.199G > C; p. c.1001T > G; p. Mutation c.320A > G; p. c.346G > C; p. c.1000T > C; p. c.898T > C; p. c.2024T > C; p.

Table 1 Clinical and molecular features of pathogenic PDE10A mutations. ND, Not done. and eventually how they might be treated.

34 E.L. Whiteley, et al. Cellular Signalling 60 (2019) 31–38

Furthermore, two sisters from an Afghan family displayed hy- [84–86 ]. As a result, these patients present with autosomal dominant perkinetic and choreatic movements, motor restlessness and hypotonia striatal degeneration, a neurologic disorder characterised by bradyki- as a consequence of biallelic mutations within the catalytic domain of nesia, dysarthria and muscle rigidity. On the contrary, PDE8B knockout PDE10A (c.2024T > C; p.Leu675Pro) [71]. This would probably affect mice exhibit improved motor performance and a reduced age-induced the ability to hydrolyse cyclic nucleotides as this amino acid forms part decline in motor coordination [87], which could be due to a different of the active site [72,73]. Similar to mutations in the GAF-A domain, striatal expression pattern than in humans or suggestive of an in- these patients showed an early manifestation of the symptoms and dependent gain of function phenotype for the truncated form of PDE8B. normal MRI scans [71], inferring a common malfunction of the enzyme An aberrant increase of cAMP related to pathogenesis can also occur activity. Finally, a compound heterozygous mutation in PDE10A out- from dysfunctional adenylyl cyclase 5 (ADCY5), the most abundant AC side the GAF domains (c.199G > C; p.E67Q and c.1873A > T; p.I625F) isoform in MSNs, responsible for integrating signals from multiple re- has been detected in one individual with childhood onset of paroxysmal ceptors including D1 and D2 striatal dopamine receptors [88]. Thus, non-kynesigenic dyskinesia [67]. In this case, the patient presented a several mutations in ADCY5 have been identified as an important cause fronto-parietal cortical atrophy without striatal degeneration, sug- of a wide range of mixed hyperkinetic abnormal movements such as gesting a prominent role of PDE10A not only in the basal ganglia but in dystonia, childhood-onset chorea and myoclonus [89]. The most re- the whole motor circuit. current missense mutation occurs at Arg418, located in the first cyto- plasmic domain close to the Gαi binding site [90] and causes a mod- erate to severe movement disorder, whilst a mutation in the catalytic 4. Defective cAMP signalling as a central mechanism in ATP–binding pocket (p.A726T) is associated with a milder phenotype hyperkinetic movement disorders/chorea [91]. These mutations have no effect on the expression of ADCY5 but they increase its catalytic activity to synthesize cAMP [92]. Moreover, As described above, mutations in PDE10A are a novel cause of hy- ADCY5-null mice with a reduction in cAMP levels exhibit hypokinetic perkinetic movement disorders, likely highlighting that cyclic nucleo- motor dysfunction with abnormal coordination, bradykinesia and lo- tide signalling in MSNs is a central mechanism underlying the patho- comotor impairment accompanied by a reduction in the expression of genesis of basal ganglia disorders. Intriguingly, many hyperkinetic the D1Rand Gsα [93]. Finally, ADCY5 haploinsufficiency by a splice site movement disorders with a genetic origin are caused by the mutation of mutation that leads to RNA instability also causes chorea and dystonia a protein involved in the regulation of cyclic nucleotides (Table 2; in patients [94]. The similar pathological manifestations caused by both Fig. 3)[74]. As we have seen, PDE10A is a major degradative enzyme ADCY5 loss- and gain-of-function mutations emphasise the complexity for cAMP and cGMP in the striatum [49], but also expressed within of cAMP signalling which orchestrates a multitude of different path- MSNs are PDE1B, PDE4B, PDE2A, PDE7B and PDE8B [19] which to- ways and the necessity to fine tune its concentration in the striatum. gether play an important role in the maintenance of cyclic nucleotide Alterations in the activity of ADCY5 by mutations in its interacting levels and compartmentalisation [75]. G proteins have also been reported to cause hyperkinetic movement fi To reinforce the convergence on these speci c pathways, a patient disorders. GNAO1 encodes the most commonly expressed G α-subunit presenting with childhood-onset chorea associated with dystonia (not (Goα) in the central nervous system which couples to GPCRs including dissimilar to the PDE10A families) was shown to carry a homozygous adenosine A1 and D2 receptors [95] and functions as an inhibitor of missense mutation in PDE2A [76]. The mutation is within the cyclic ADCYs [96]. There are three mutation hotspots in GNAO1 associated nucleotide binding pocket of the GAF-B domain (p.D480G) and results with an early-onset chorea and dystonia phenotype (Gly203, Arg209 in a severe decrease in the dual enzymatic activity of PDE2A, which in and Glu246), which are important for the stabilisation of the Gα-con- the striatum has a strong preference for cGMP [80]. There is clearly taining complexes, mainly in GTP-bound active states, and locate in the much more functional characterisation that needs to be done with this region that partially overlaps with the putative ADCY binding site [97]. mutation. It will also be important to understand how a mutation in The resultant mutant proteins exhibit a higher activity, inhibiting ADCY ff ff ff di erent GAF domains in di erent PDEs leads to di erences in phe- and therefore decrease cAMP levels [98]. Dystonia has also been re- notypic clinical presentation. At the moment, some progress has been ported to be caused by mutations in GNAL which encodes the α-subunit made with the underlying mechanisms of mutations in the GAF do- of Golf [99,100]. Gαolf is strongly expressed in the striatum, specifically mains of PDE6 that lead to retinitis pigmentosa, achromatopsia and in the striosome compartment [101], where it may couple to adenosine autosomal dominant congenital stationary night blindness. Thus, mu- A2A and D1 receptors to activate ADCY5 [102]. Pathological mutations tations R104W located in the GAF-A domain and Y323N and P391L in of GNAL lead to unstable truncated proteins, complete deficiency of GAF-B cause an increase proteolytic degradation of PDE6C [81] while functional activity [100] or impaired binding to D1Rs [103]. Further- γ H262N mutant disrupts the inhibitory interaction of P reducing its more, some mutations in the G-protein β subunit encoded by GNB1 ability to promote the enzyme folding [82]. Moreover, these changes have also been associated with dystonia [104]. The mutations in GNB1 could be the result of an aberrant compartmentalisation, as the GAF-A are primarily located in exons 6 and 7 which express the binding sur- domain of PDE6 contains a rod outer segment localization signal face for interactions with Gα and several downstream effectors, po- ff [83].Three di erent mutations in PDE8B, found in German, Japanese tentially affecting the production of cAMP [105,106]. Likewise, at the and Portuguese families, produce a truncated enzyme with loss of all receptor level, a mutation resulting in GPR88 truncation has been functional domains and complete ablation of cAMP hydrolysing ability

Table 2 Other PDEs implicated in hyperkinetic movement disorders.

PDE Disease Organism Biochemical impact on PDEs Reference

PDE1B HD R6/1, R6/2 and Q175 mice Decline in mRNA levels in the striatum [36,58] PDE2A (recessive mutation in c.1439A > G; Childhood-onset choreo- Human (Spanish male Severe decreased enzymatic activity [76,77] p.Asp480Gly) dystonia patient) PDE4B HD R6/2 mice Increased enzymatic activity in the cortex and [78] striatum PDE4AX HD R6/1 mice Reduction in protein levels in the hippocampus [79] PDE4D1 HD R6/1 mice Reduction in protein levels in the hippocampus [79] PDE4D3 HD R6/1 mice Reduction in protein levels in the hippocampus [79]

35 E.L. Whiteley, et al. Cellular Signalling 60 (2019) 31–38

Fig. 3. Dysregulation of cAMP signalling in MSNs is associated with hyperkinetic movement disorders. Mutations in genes implicated in the synthesis, degradation or distribution of cyclic nucleotides in the striatonigral and striatopallidal neurons (represented in blue and red respectively) have been identified as causes of hyperkinetic movement disorders. cAMP synthesis in the striatum is primarily controlled by ADCY5, which has been associated with hereditary chorea. Regulation of this enzyme by G proteins is also critical in coordinated movement. Thus, mutations in GNAO1 that expresses the inhibitory Goα, in GNAL that encodes the Golfα subunit or in the β subunit-encoding gene GNB1, can lead to a dystonia phenotype. Furthermore, an aberrant function of the purine metabolic enzyme HPRT or the GPCR GPR88 are also related to a genetic origin of chorea. The compartmentalisation of PDEs shapes the local gradients of cyclic nucleotides in the striatum, which are essential for the regulation of the motor function. Accordingly, several pathogenic substitutions in these cAMP degradative enzymes induce movement disorders, such as PDE2A, PDE8B and especially PDE10A. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.) identified in a family with early-onset chorea [107]. This orphan GPCR obvious structural deficits as shown by MRI while the GAF-B patients is abundantly expressed both in D1R- and D2R- containing MSNs [108] show abnormal bilateral hyperintense lesions. There have been no and acts through a Gi protein to inhibit cAMP accumulation [109]. studies to date, in cell systems or model organisms, where the two − − Similarly, Gpr88 / mice show hyperactivity and motor coordination classes of mutations have been compared. These types of studies will be deficits [110,111]. The intimate relationship between hyperkinetic essential in the future to decipher how these mutations relate to disease movement disorders and aberrant cyclic nucleotide signalling unveil pathology and to the understanding of how they manifest in patients. that cAMP/cGMP pathways could have a more prominent role in other Comprehension of the molecular mechanisms within the cAMP and neurological diseases with coordinated movement alterations. For in- cGMP signalling systems perturbed by PDE10A GAF mutations may also stance, the cAMP cascade is impaired in Lesch-Nyhan syndrome (LSN), inform the direction of novel therapeutic strategies that may alleviate a neurological disease with mental retardation, dystonia and chorea symptoms in patients affected by the movement disorders described caused by mutations in the gene encoding the hypoxanthine-guanine above. One concept that may be germane in this context is the devel- phosphoribosyltransferase (HPRT) [112]. LSN patients exhibit a opment of PDE10A activators. This could be achieved pharmacologi- marked loss of striatal dopaminergic fibres without MSNs degeneration cally using compounds that potentially lock PDE10A in an active con- [113]. Accordingly, the HPRT knockout mice also display abnormal formation akin to that when cAMP is bound to the GAF domain. striatal architecture [114] that could be related to the increased ex- Bacterial, viral and plant GAF domains are known to associate with a pression of PDE10A and reduction of other cAMP effectors such as varied collection of small molecules that are structurally unrelated to DARPP-32 [115]. cyclic nucleotides [116] and PDEs are the only family of mammalian proteins that contain such domains [117]. The divergence between fi 5. Concluding remarks mammalian PDE GAF domains should also allow speci city of action if GAF activator compounds can be discovered. Another possible route to fi A convergence of human mutations driving hyperkinetic clinical PDE10A enhancement would be viral transfer of PDE genes to speci c disorders on components of the cAMP and cGMP regulatory networks brain regions. This strategy is currently being used for PDE6 in the highlights the importance of tuning levels and maintaining the correct retina where a loss of PDE6 activity promotes retinal degeneration cellular compartmentalisation of these critical second messenger mo- [118]. Delivery of PDE6 using AAV8 stabilised retinal cGMP con- lecules. This article has considered the consequences of mutations in centrations in canine retinas and served to protect rods and cones from the regulatory GAF domains of PDE10A. The GAF-A and GAF-B grouped deterioration. If optogenetic delivery of PDE10A virus could be mutations present quite similarly, but the GAF-A biallelic mutations achieved, the spatial and temporal control of cyclic nucleotide levels in seem more severe including an earlier age of onset and in general a distinct brain regions could be orchestrated by restricted light emission ff more complex set of clinical issues. Interestingly however, they have no and this would certainly guard against side-e ects associated with

36 E.L. Whiteley, et al. Cellular Signalling 60 (2019) 31–38 systemic administration of pharmaceuticals that concomitantly change 9027–9037. the activity of a PDE family in all organs, tissues and cellular locations. [35] C.J. Schmidt, D.S. Chapin, J. Cianfrogna, M.L. Corman, M. Hajos, J.F. Harms, W.E. Hoff man, L.A. Lebel, S.A. McCarthy, F.R. Nelson, C. Proulx-LaFrance, M.J. Majchrzak, A.D. Ramirez, K. Schmidt, P.A. Seymour, J.A. Siuciak, Conflict of interest/competing interests F.D. Tingley 3rd, R.D. Williams, P.R. Verhoest, F.S. Menniti, J. Pharmacol. Exp. Ther. 325 (2008) 681–690. [36] A.L. Hebb, H.A. Robertson, E.M. Denovan-Wright, Neuroscience 123 (2004) NJB was a full-time employee and shareholder of AstraZeneca at the 967–981. time of writing of this review. [37] H. Hu, E.A. McCaw, A.L. Hebb, G.T. Gomez, E.M. Denovan-Wright, Eur. J. GSB is a Director of Portage Glasgow Ltd. Neurosci. 20 (2004) 3351–3363. [38] A.M. Garcia, M. Redondo, A. Martinez, C. Gil, Curr. Med. Chem. 21 (2014) 1171–1187. Acknowledgements [39] K. Fujishige, J. Kotera, H. Michibata, K. Yuasa, S. Takebayashi, K. Okumura, K. Omori, J. Biol. Chem. 274 (1999) 18438–18445. EW was funded by AstraZeneca. GST is a fellow of the AstraZeneca [40] K. Loughney, P.B. Snyder, L. Uher, G.J. Rosman, K. Ferguson, V.A. Florio, Gene 234 (1999) 109–117. postdoc programme. [41] S.H. Soderling, S.J. Bayuga, J.A. Beavo, Proc. Natl. Acad. Sci. U. S. A. 96 (1999) 7071–7076. References [42] T.M. Coskran, D. Morton, F.S. Menniti, W.O. Adamowicz, R.J. Kleiman, A.M. Ryan, C.A. Strick, C.J. Schmidt, D.T. Stephenson, J. Histochem. Cytochem. 54 (2006) 1205–1213. [1] T.D. Sanger, D. Chen, D.L. Fehlings, M. Hallett, A.E. Lang, J.W. Mink, H.S. Singer, [43] C.M. MacMullen, K. Vick, R. Pacifico, M. Fallahi-Sichani, R.L. Davis, Transl. K. Alter, H. Ben-Pazi, E.E. Butler, R. Chen, A. Collins, S. Dayanidhi, H. Forssberg, Psychiatry 6 (2016) e742. E. Fowler, D.L. Gilbert, S.L. Gorman, M.E. Gormley Jr., H.A. Jinnah, B. Kornblau, [44] J.M. Passner, S.C. Schultz, T.A. Steitz, J. Mol. Biol. 304 (2000) 847–859. K.J. Krosschell, R.K. Lehman, C. MacKinnon, C.J. Malanga, R. Mesterman, [45] S.E. Martinez, A.Y. Wu, N.A. Glavas, X.B. Tang, S. Turley, W.G. Hol, J.A. Beavo, M.B. Michaels, T.S. Pearson, J. Rose, B.S. Russman, D. Sternad, K.J. Swoboda, Proc. Natl. Acad. Sci. U. S. A. 99 (2002) 13260–13265. F. Valero-Cuevas, Mov. Disord. 25 (2010) 1538–1549. [46] A.Y. Wu, X.B. Tang, S.E. Martinez, K. Ikeda, J.A. Beavo, J. Biol. Chem. 279 (2004) [2] J. Jankovic, Lancet Neurol. 8 (2009) 844–856. 37928–37938. [3] A.M. Graybiel, S.T. Grafton, Cold Spring Harb. Perspect. Biol. 7 (2015) a021691. [47] R. Zoraghi, J.D. Corbin, S.H. Francis, Mol. Pharmacol. 65 (2004) 267–278. [4] A.M. Graybiel, Curr. Biol. 10 (2000) R509–R511. [48] L. Liu, T. Underwood, H. Li, R. Pamukcu, W.J. Thompson, Cell. Signal. 14 (2002) [5] J.C. Hedreen, S.E. Folstein, J. Neuropathol. Exp. Neurol. 54 (1995) 105–120. 45–51. [6] A.C. Kreitzer, Annu. Rev. Neurosci. 32 (2009) 127–147. [49] C. Russwurm, D. Koesling, M. Russwurm, J. Biol. Chem. 290 (2015) 11936–11947. [7] H. Ho, M. Both, A. Siniard, S. Sharma, J.H. Notwell, M. Wallace, D.P. Leone, [50] Y.P. Deng, R.L. Albin, J.B. Penney, A.B. Young, K.D. Anderson, A. Reiner, J. Chem. A. Nguyen, E. Zhao, H. Lee, D. Zwilling, K.R. Thompson, S.P. Braithwaite, Neuroanat. 27 (2004) 143–164. M. Huentelman, T. Portmann, Front. Cell. Neurosci. 12 (2018) 159. [51] N. Reedeker, R.C. Van Der Mast, E.J. Giltay, E. Van Duijn, R.A. Roos, Mov. Disord. [8] O. Gokce, G.M. Stanley, B. Treutlein, N.F. Neff, J.G. Camp, R.C. Malenka, 25 (2010) 1612–1618. P.E. Rothwell, M.V. Fuccillo, T.C. Sudhof, S.R. Quake, Cell Rep. 16 (2016) [52] S. Gines, I.S. Seong, E. Fossale, E. Ivanova, F. Trettel, J.F. Gusella, V.C. Wheeler, 1126–1137. F. Persichetti, M.E. MacDonald, Hum. Mol. Genet. 12 (2003) 497–508. [9] S.N. Haber, J. Chem. Neuroanat. 26 (2003) 317–330. [53] R. Ahmad, S. Bourgeois, A. Postnov, M.E. Schmidt, G. Bormans, K. Van Laere, [10] A.V. Kravitz, L.D. Tye, A.C. Kreitzer, Nat. Neurosci. 15 (2012) 816–818. W. Vandenberghe, Neurology 82 (2014) 279–281. [11] J.P. Schulke, N.J. Brandon, Adv. Neurobiol. 17 (2017) 15–43. [54] H. Wilson, F. Niccolini, S. Haider, T.R. Marques, G. Pagano, C. Coello, S. Natesan, [12] J.A. Beavo, L.L. Brunton, Nat. Rev. Mol. Cell Biol. 3 (2002) 710–718. S. Kapur, E.A. Rabiner, R.N. Gunn, S.J. Tabrizi, M. Politis, J. Neurol. Sci. 368 [13] G.M. Fimia, P. Sassone-Corsi, J. Cell Sci. 114 (2001) 1971–1972. (2016) 243–248. [14] M. Kuhn, Physiol. Rev. 96 (2016) 751–804. [55] F. Niccolini, T. Foltynie, T. Reis Marques, N. Muhlert, A.C. Tziortzi, G.E. Searle, [15] L.R. Potter, Cell. Signal. 23 (2011) 1921–1926. S. Natesan, S. Kapur, E.A. Rabiner, R.N. Gunn, P. Piccini, M. Politis, Brain 138 [16] C.M. MacMullen, M. Fallahi, R.L. Davis, Gene 606 (2017) 17–24. (2015) 3003–3015. [17] W. Conti MaR, West NJBaAR, Cyclic-Nucleotide Phosphodiesterases in the Central [56] D.S. Russell, D.L. Jennings, O. Barret, G.D. Tamagnan, V.M. Carroll, F. Caille, Nervous System, (2014), pp. 1–46. D. Alagille, T.J. Morley, C. Papin, J.P. Seibyl, K.L. Marek, Neurology 86 (2016) [18] G.S. Baillie, FEBS J. 276 (2009) 1790–1799. 748–754. [19] V. Lakics, E.H. Karran, F.G. Boess, Neuropharmacology 59 (2010) 367–374. [57] A. Harada, K. Suzuki, H. Kimura, J. Pharmacol. Exp. Ther. 360 (2017) 75–83. [20] M.P. Kelly, W. Adamowicz, S. Bove, A.J. Hartman, A. Mariga, G. Pathak, [58] V. Beaumont, S. Zhong, H. Lin, W. Xu, A. Bradaia, E. Steidl, M. Gleyzes, K. Wadel, V. Reinhart, A. Romegialli, R.J. Kleiman, Cell. Signal. 26 (2014) 383–397. B. Buisson, F.E. Padovan-Neto, S. Chakroborty, K.M. Ward, J.F. Harms, J. Beltran, [21] M.P. Kelly, West NJBaAR, Cyclic-Nucleotide Phosphodiesterases in the Central M. Kwan, A. Ghavami, J. Haggkvist, M. Toth, C. Halldin, A. Varrone, C. Schaab, Nervous System, (2014), pp. 47–58. J.N. Dybowski, S. Elschenbroich, K. Lehtimaki, T. Heikkinen, L. Park, J. Rosinski, [22] K. Fujishige, J. Kotera, K. Omori, Eur. J. Biochem. 266 (1999) 1118–1127. L. Mrzljak, D. Lavery, A.R. West, C.J. Schmidt, M.M. Zaleska, I. Munoz-Sanjuan, [23] R. Jager, C. Russwurm, F. Schwede, H.G. Genieser, D. Koesling, M. Russwurm, J. Neuron 92 (2016) 1220–1237. Biol. Chem. 287 (2012) 1210–1219. [59] C. Giampa, D. Laurenti, S. Anzilotti, G. Bernardi, F.S. Menniti, F.R. Fusco, PLoS [24] H. Dong, K.P. Claffey, S. Brocke, P.M. Epstein, Breast Cancer Res. Treat. 152 One 5 (2010) e13417. (2015) 17–28. [60] C. Giampa, S. Patassini, A. Borreca, D. Laurenti, F. Marullo, G. Bernardi, [25] B. Zhu, A. Lindsey, N. Li, K. Lee, V. Ramirez-Alcantara, J.C. Canzoneri, A. Fajardo, F.S. Menniti, F.R. Fusco, Neurobiol. Dis. 34 (2009) 450–456. L. Madeira da Silva, M. Thomas, J.T. Piazza, L. Yet, B.T. Eberhardt, E. Gurpinar, [61] A. Giralt, A. Saavedra, O. Carreton, H. Arumi, S. Tyebji, J. Alberch, E. Perez- D. Otali, W. Grizzle, J. Valiyaveettil, X. Chen, A.B. Keeton, G.A. Piazza, Oncotarget Navarro, Hippocampus 23 (2013) 684–695. 8 (2017) 69264–69280. [62] M. Delnomdedieu, Y. Tan, A. Ogden, Z. Berger, R. Reilmann, J. Neurol. Neurosurg. [26] N. Li, X. Chen, B. Zhu, V. Ramirez-Alcantara, J.C. Canzoneri, K. Lee, S. Sigler, Psychiatry 89 (2018) A99–A100. B. Gary, Y. Li, W. Zhang, M.P. Moyer, E.A. Salter, A. Wierzbicki, A.B. Keeton, [63] C.P. Diggle, S.J. Sukoff Rizzo, M. Popiolek, R. Hinttala, J.P. Schulke, M.A. Kurian, G.A. Piazza, Oncotarget 6 (2015) 27403–27415. I.M. Carr, A.F. Markham, D.T. Bonthron, C. Watson, S.M. Sharif, V. Reinhart, [27] T.F. Seeger, B. Bartlett, T.M. Coskran, J.S. Culp, L.C. James, D.L. Krull, J. Lanfear, L.C. James, M.A. Vanase-Frawley, E. Charych, M. Allen, J. Harms, C.J. Schmidt, A.M. Ryan, C.J. Schmidt, C.A. Strick, A.H. Varghese, R.D. Williams, P.G. Wylie, J. Ng, K. Pysden, C. Strick, P. Vieira, K. Mankinen, H. Kokkonen, M. Kallioinen, F.S. Menniti, Brain Res. 985 (2003) 113–126. R. Sormunen, J.O. Rinne, J. Johansson, K. Alakurtti, L. Huilaja, T. Hurskainen, [28] A. Nishi, M. Kuroiwa, D.B. Miller, J.P. O'Callaghan, H.S. Bateup, T. Shuto, K. Tasanen, E. Anttila, T.R. Marques, O. Howes, M. Politis, S. Fahiminiya, N. Sotogaku, T. Fukuda, N. Heintz, P. Greengard, G.L. Snyder, J. Neurosci. 28 K.Q. Nguyen, J. Majewski, J. Uusimaa, E. Sheridan, N.J. Brandon, Am. J. Hum. (2008) 10460–10471. Genet. 98 (2016) 735–743. [29] S.M. Grauer, V.L. Pulito, R.L. Navarra, M.P. Kelly, C. Kelley, R. Graf, B. Langen, [64] S. Esposito, M. Carecchio, D. Tonduti, V. Saletti, C. Panteghini, L. Chiapparini, S. Logue, J. Brennan, L. Jiang, E. Charych, U. Egerland, F. Liu, K.L. Marquis, G. Zorzi, C. Pantaleoni, B. Garavaglia, D. Krainc, S.J. Lubbe, N. Nardocci, M. Malamas, T. Hage, T.A. Comery, N.J. Brandon, J. Pharmacol. Exp. Ther. 331 N.E. Mencacci, Mov. Disord. 32 (2017) 1646–1647. (2009) 574–590. [65] N.E. Mencacci, E.J. Kamsteeg, K. Nakashima, L. R'Bibo, D.S. Lynch, B. Balint, [30] S. Threlfell, S. Sammut, F.S. Menniti, C.J. Schmidt, A.R. West, J. Pharmacol. Exp. M.A. Willemsen, M.E. Adams, S. Wiethoff, K. Suzuki, C.H. Davies, J. Ng, E. Meyer, Ther. 328 (2009) 785–795. L. Veneziano, P. Giunti, D. Hughes, F.L. Raymond, M. Carecchio, G. Zorzi, [31] C.A. Strick, L.C. James, C.B. Fox, T.F. Seeger, F.S. Menniti, C.J. Schmidt, N. Nardocci, C. Barzaghi, B. Garavaglia, V. Salpietro, J. Hardy, A.M. Pittman, Neuropharmacology 58 (2010) 444–451. H. Houlden, M.A. Kurian, H. Kimura, L.E. Vissers, N.W. Wood, K.P. Bhatia, Am. J. [32] J. Kotera, T. Sasaki, T. Kobayashi, K. Fujishige, Y. Yamashita, K. Omori, J. Biol. Hum. Genet. 98 (2016) 763–771. Chem. 279 (2004) 4366–4375. [66] D.L. Narayanan, D. Deshpande, A. Das Bhowmik, D.R. Varma, A. Dalal, Am. J. [33] Z. Xie, W.O. Adamowicz, W.D. Eldred, A.B. Jakowski, R.J. Kleiman, D.G. Morton, Med. Genet. A 176 (2018) 146–150. D.T. Stephenson, C.A. Strick, R.D. Williams, F.S. Menniti, Neuroscience 139 [67] F. Niccolini, N.E. Mencacci, T. Yousaf, E.A. Rabiner, V. Salpietro, G. Pagano, (2006) 597–607. B. Balint, S. Efthymiou, H. Houlden, R.N. Gunn, N. Wood, K.P. Bhatia, M. Politis, [34] E.I. Charych, L.X. Jiang, F. Lo, K. Sullivan, N.J. Brandon, J. Neurosci. 30 (2010) Mov. Disord. 33 (2018) 1961–1965.

37 E.L. Whiteley, et al. Cellular Signalling 60 (2019) 31–38

[68] G.J. Harris, E.H. Aylward, C.E. Peyser, G.D. Pearlson, J. Brandt, J.V. Roberts- 18706–18711. Twillie, P.E. Barta, S.E. Folstein, Arch. Neurol. 53 (1996) 316–324. [96] M.H. Ghahremani, P. Cheng, P.M. Lembo, P.R. Albert, J. Biol. Chem. 274 (1999) [69] M. Gross-Langenhoff, K. Hofbauer, J. Weber, A. Schultz, J.E. Schultz, J. Biol. 9238–9245. Chem. 281 (2006) 2841–2846. [97] H. Saitsu, R. Fukai, B. Ben-Zeev, Y. Sakai, M. Mimaki, N. Okamoto, Y. Suzuki, [70] N. Handa, E. Mizohata, S. Kishishita, M. Toyama, S. Morita, T. Uchikubo-Kamo, Y. Monden, H. Saito, B. Tziperman, M. Torio, S. Akamine, N. Takahashi, H. Osaka, R. Akasaka, K. Omori, J. Kotera, T. Terada, M. Shirouzu, S. Yokoyama, J. Biol. T. Yamagata, K. Nakamura, Y. Tsurusaki, M. Nakashima, N. Miyake, M. Shiina, Chem. 283 (2008) 19657–19664. K. Ogata, N. Matsumoto, Eur. J. Hum. Genet. 24 (2016) 129–134. [71] C. Knopp, M. Hausler, B. Muller, R. Damen, A. Stoppe, M. Mull, M. Elbracht, [98] H. Feng, B. Sjogren, B. Karaj, V. Shaw, A. Gezer, R.R. Neubig, Neurology 89 (2017) I. Kurth, M. Begemann, Parkinsonism Relat. Disord. (2019), https://doi.org/10. 762–770. 1016/j.parkreldis.2019.02.007. [99] K.R. Kumar, K. Lohmann, I. Masuho, R. Miyamoto, A. Ferbert, T. Lohnau, [72] H. Ke, H. Wang, M. Ye, Handbook of Experimental Pharmacology, (2011), pp. M. Kasten, J. Hagenah, N. Bruggemann, J. Graf, A. Munchau, V.S. Kostic, C.M. Sue, 121–134. A.R. Domingo, R.L. Rosales, L.V. Lee, K. Freimann, A. Westenberger, Y. Mukai, [73] H. Wang, Y. Liu, J. Hou, M. Zheng, H. Robinson, H. Ke, Proc. Natl. Acad. Sci. U. S. T. Kawarai, R. Kaji, C. Klein, K.A. Martemyanov, A. Schmidt, JAMA Neurol. 71 A. 104 (2007) 5782–5787. (2014) 490–494. [74] M. Carecchio, N.E. Mencacci, Curr. Neurol. Neurosci. Rep. 17 (2017) 97. [100] T. Fuchs, R. Saunders-Pullman, I. Masuho, M.S. Luciano, D. Raymond, S. Factor, [75] S.R. Neves-Zaph, Adv. Neurobiol. 17 (2017) 3–14. A.E. Lang, T.W. Liang, R.M. Trosch, S. White, E. Ainehsazan, D. Herve, N. Sharma, [76] V. Salpietro, B. Perez-Duenas, K. Nakashima, V. San Antonio-Arce, A. Manole, M.E. Ehrlich, K.A. Martemyanov, S.B. Bressman, L.J. Ozelius, Nat. Genet. 45 S. Efthymiou, J. Vandrovcova, C. Bettencourt, N.E. Mencacci, C. Klein, M.P. Kelly, (2013) 88–92. C.H. Davies, H. Kimura, A. Macaya, H. Houlden, Mov. Disord. 33 (2018) 482–488. [101] W. Sako, R. Morigaki, S. Nagahiro, R. Kaji, S. Goto, Neuroscience 170 (2010) [77] S. Candela, M.I. Vanegas, A. Darling, J.D. Ortigoza-Escobar, M. Alamar, 497–502. J. Muchart, A. Climent, E. Ferrer, J. Rumia, B. Perez-Duenas, J. Neurosurg. [102] J.C. Corvol, J.M. Studler, J.S. Schonn, J.A. Girault, D. Herve, J. Neurochem. 76 Pediatr. 22 (2018) 416–425. (2001) 1585–1588. [78] M. Tanaka, K. Ishizuka, Y. Nekooki-Machida, R. Endo, N. Takashima, H. Sasaki, [103] I. Masuho, M. Fang, C. Geng, J. Zhang, H. Jiang, R.K. Ozgul, D.Y. Yilmaz, Y. Komi, A. Gathercole, E. Huston, K. Ishii, K.K. Hui, M. Kurosawa, S.H. Kim, D. Yalnizoglu, D. Yuksel, A. Yarrow, A. Myers, S.C. Burn, P.L. Crotwell, S. Padilla- N. Nukina, E. Takimoto, M.D. Houslay, A. Sawa, J. Clin. Invest. 127 (2017) Lopez, A. Dursun, K.A. Martemyanov, M.C. Kruer, Neurol. Genet. 2 (2016) e78. 1438–1450. [104] P. Hemati, A. Revah-Politi, H. Bassan, S. Petrovski, C.G. Bilancia, K. Ramsey, [79] A. Giralt, A. Saavedra, O. Carreton, X. Xifro, J. Alberch, E. Perez-Navarro, Hum. N.G. Griffin, L. Bier, M.T. Cho, M. Rosello, S.A. Lynch, S. Colombo, A. Weber, Mol. Genet. 20 (2011) 4232–4247. M. Haug, E.L. Heinzen, T.T. Sands, V. Narayanan, M. Primiano, V.S. Aggarwal, [80] A.T. Bender, J.A. Beavo, Pharmacol. Rev. 58 (2006) 488–520. F. Millan, S.G. Sattler-Holtrop, A. Caro-Llopis, N. Pillar, J. Baker, R. Freedman, [81] P. Cheguru, A. Majumder, N.O. Artemyev, Mol. Cell. Neurosci. 64 (2015) 1–8. H.Y. Kroes, S. Sacharow, N. Stong, P. Lapunzina, M.C. Schneider, [82] K.N. Gopalakrishna, K. Boyd, N.O. Artemyev, Cell. Signal. 37 (2017) 74–80. N.J. Mendelsohn, A. Singleton, V. Loik Ramey, K. Wou, A. Kuzminsky, S. Monfort, [83] P. Cheguru, Z. Zhang, N.O. Artemyev, J. Neurochem. 129 (2014) 256–263. M. Weiss, S. Doyle, A. Iglesias, F. Martinez, F. McKenzie, C. Orellana, K.L.I. van [84] S. Appenzeller, A. Schirmacher, H. Halfter, S. Baumer, M. Pendziwiat, Gassen, M. Palomares, L. Bazak, A. Lee, A. Bircher, L. Basel-Vanagaite, V. Timmerman, P. De Jonghe, K. Fekete, F. Stogbauer, P. Ludemann, M. Hund, M. Hafstrom, G. Houge, Group CRR, Study DDD, D.B. Goldstein, K. Anyane-Yeboa, E.S. Quabius, E.B. Ringelstein, G. Kuhlenbaumer, Am. J. Hum. Genet. 86 (2010) Am. J. Med. Genet. A 176 (2018) 2259–2275. 83–87. [105] C.E. Ford, N.P. Skiba, H. Bae, Y. Daaka, E. Reuveny, L.R. Shekter, R. Rosal, [85] R. Azuma, K. Ishikawa, K. Hirata, Y. Hashimoto, M. Takahashi, K. Ishii, A. Inaba, G. Weng, C.S. Yang, R. Iyengar, R.J. Miller, L.Y. Jan, R.J. Lefkowitz, H.E. Hamm, T. Yokota, S. Orimo, Mov. Disord. 30 (2015) 1964–1967. Science 280 (1998) 1271–1274. [86] O.G. Barsottini, M. Martins Pde, H.F. Chien, S. Raskin, R.H. Nunes, A.J. da Rocha, [106] S. Petrovski, S. Kury, C.T. Myers, K. Anyane-Yeboa, B. Cogne, M. Bialer, F. Xia, J.L. Pedroso, Neurology 85 (2015) 1816–1818. P. Hemati, J. Riviello, M. Mehaffey, T. Besnard, E. Becraft, A. Wadley, A.R. Politi, [87] L.C. Tsai, G.C. Chan, S.N. Nangle, M. Shimizu-Albergine, G.L. Jones, D.R. Storm, S. Colombo, X. Zhu, Z. Ren, I. Andrews, T. Dudding-Byth, A.L. Schneider, J.A. Beavo, L.S. Zweifel, Genes Brain Behav. 11 (2012) 837–847. G. Wallace, University of Washington Center for Mendelian G, A.B.I. Rosen, [88] I. Matsuoka, Y. Suzuki, N. Defer, H. Nakanishi, J. Hanoune, J. Neurochem. 68 S. Schelley, G.M. Enns, P. Corre, J. Dalton, S. Mercier, X. Latypova, S. Schmitt, (1997) 498–506. E. Guzman, C. Moore, L. Bier, E.L. Heinzen, P. Karachunski, N. Shur, T. Grebe, [89] M. Carecchio, N.E. Mencacci, A. Iodice, R. Pons, C. Panteghini, G. Zorzi, F. Zibordi, A. Basinger, J.M. Nguyen, S. Bezieau, K. Wierenga, J.A. Bernstein, I.E. Scheffer, A. Bonakis, A. Dinopoulos, J. Jankovic, L. Stefanis, K.P. Bhatia, V. Monti, L. R'Bibo, J.A. Rosenfeld, H.C. Mefford, B. Isidor, D.B. Goldstein, Am. J. Hum. Genet. 98 L. Veneziano, B. Garavaglia, C. Fusco, N. Wood, M. Stamelou, N. Nardocci, (2016) 1001–1010. Parkinsonism Relat. Disord. 41 (2017) 37–43. [107] F. Alkufri, A. Shaag, B. Abu-Libdeh, O. Elpeleg, Neurol. Genet. 2 (2016) e64. [90] C.W. Dessauer, J.J. Tesmer, S.R. Sprang, A.G. Gilman, J. Biol. Chem. 273 (1998) [108] A. Quintana, E. Sanz, W. Wang, G.P. Storey, A.D. Guler, M.J. Wanat, B.A. Roller, 25831–25839. A. La Torre, P.S. Amieux, G.S. McKnight, N.S. Bamford, R.D. Palmiter, Nat. [91] D.H. Chen, A. Meneret, J.R. Friedman, O. Korvatska, A. Gad, E.S. Bonkowski, Neurosci. 15 (2012) 1547–1555. H.A. Stessman, D. Doummar, C. Mignot, M. Anheim, S. Bernes, M.Y. Davis, [109] C. Jin, A.M. Decker, X.P. Huang, B.P. Gilmour, B.E. Blough, B.L. Roth, Y. Hu, N. Damon-Perriere, B. Degos, D. Grabli, D. Gras, F.M. Hisama, K.M. Mackenzie, J.B. Gill, X.P. Zhang, ACS Chem. Neurosci. 5 (2014) 576–587. P.D. Swanson, C. Tranchant, M. Vidailhet, S. Winesett, O. Trouillard, [110] S.F. Logue, S.M. Grauer, J. Paulsen, R. Graf, N. Taylor, M.A. Sung, L. Zhang, L.M. Amendola, M.O. Dorschner, M. Weiss, E.E. Eichler, A. Torkamani, E. Roze, Z. Hughes, V.L. Pulito, F. Liu, S. Rosenzweig-Lipson, N.J. Brandon, K.L. Marquis, T.D. Bird, W.H. Raskind, Neurology 85 (2015) 2026–2035. B. Bates, M. Pausch, Mol. Cell. Neurosci. 42 (2009) 438–447. [92] Y.Z. Chen, J.R. Friedman, D.H. Chen, G.C. Chan, C.S. Bloss, F.M. Hisama, [111] A.C. Meirsman, J. Le Merrer, L.P. Pellissier, J. Diaz, D. Clesse, B.L. Kieffer, S.E. Topol, A.R. Carson, P.H. Pham, E.S. Bonkowski, E.R. Scott, J.K. Lee, G. Zhang, J.A. Becker, Biol. Psychiatry 79 (2016) 917–927. G. Oliveira, J. Xu, A.A. Scott-Van Zeeland, Q. Chen, S. Levy, E.J. Topol, D. Storm, [112] G.H. Guibinga, F. Murray, N. Barron, PLoS One 8 (2013) e63333. P.D. Swanson, T.D. Bird, N.J. Schork, W.H. Raskind, A. Torkamani, Ann. Neurol. [113] M. Ernst, A.J. Zametkin, J.A. Matochik, D. Pascualvaca, P.H. Jons, K. Hardy, 75 (2014) 542–549. J.G. Hankerson, D.J. Doudet, R.M. Cohen, N. Engl. J. Med. 334 (1996) 1568–1572. [93] T. Iwamoto, S. Okumura, K. Iwatsubo, J. Kawabe, K. Ohtsu, I. Sakai, Y. Hashimoto, [114] I. Mikolaenko, L.M. Rao, R.C. Roberts, B. Kolb, H.A. Jinnah, Neurobiol. Dis. 20 A. Izumitani, K. Sango, K. Ajiki, Y. Toya, S. Umemura, Y. Goshima, N. Arai, (2005) 479–490. S.F. Vatner, Y. Ishikawa, J. Biol. Chem. 278 (2003) 16936–16940. [115] G.H. Guibinga, N. Barron, W. Pandori, PLoS One 9 (2014) e96575. [94] R. Carapito, N. Paul, M. Untrau, M. Le Gentil, L. Ott, G. Alsaleh, P. Jochem, [116] J.E. Schultz, Handbook of Experimental Pharmacology, (2009), pp. 93–109. M. Radosavljevic, C. Le Caignec, A. David, P. Damier, B. Isidor, S. Bahram, Mov. [117] S.H. Francis, M.A. Blount, J.D. Corbin, Physiol. Rev. 91 (2011) 651–690. Disord. 30 (2015) 423–427. [118] W.T. Deng, S. Kolandaivelu, A. Dinculescu, J. Li, P. Zhu, V.A. Chiodo, [95] M. Nobles, A. Benians, A. Tinker, Proc. Natl. Acad. Sci. U. S. A. 102 (2005) V. Ramamurthy, W.W. Hauswirth, Front. Mol. Neurosci. 11 (2018) 233.