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Augmenting CNS Glucocerebrosidase Activity As a Therapeutic Strategy for Parkinsonism and Other Gaucher-Related Synucleinopathie

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Augmenting CNS Glucocerebrosidase Activity As a Therapeutic Strategy for Parkinsonism and Other Gaucher-Related Synucleinopathie Augmenting CNS glucocerebrosidase activity as SEE COMMENTARY a therapeutic strategy for parkinsonism and other Gaucher-related synucleinopathies S. Pablo Sardia,1, Jennifer Clarkea, Catherine Viela, Monyrath Chana, Thomas J. Tamsetta, Christopher M. Treleavena, Jie Bua, Lindsay Sweeta, Marco A. Passinia, James C. Dodgea, W. Haung Yub, Richard L. Sidmanc,1, Seng H. Chenga, and Lamya S. Shihabuddina aGenzyme, a Sanofi Company, Framingham, MA 01701; bTaub Institute for Research on Alzheimer’s Disease, Columbia University Medical Center, NY 10032; and cBeth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215 Contributed by Richard L. Sidman, December 7, 2012 (sent for review September 14, 2012) Mutations of GBA1, the gene encoding glucocerebrosidase, repre- samples from patients with PD and DLB (regardless of whether sent a common genetic risk factor for developing the synucleino- they harbor mutations in GBA1), suggesting that a reduction in pathies Parkinson disease (PD) and dementia with Lewy bodies. PD glucocerebrosidase activity may contribute to the development of patients with or without GBA1 mutations also exhibit lower enzy- synucleinopathies (13–15). matic levels of glucocerebrosidase in the central nervous system A role for glucocerebrosidase in the development of synuclei- (CNS), suggesting a possible link between the enzyme and the nopathies is further supported by clinical observations of patients development of the disease. Previously, we have shown that early with Gaucher-associated parkinsonism. These individuals present treatment with glucocerebrosidase can modulate α-synuclein ag- with increased frequencies and severities of nonmotor symptoms gregation in a presymptomatic mouse model of Gaucher-related (e.g., cognitive impairment) that substantially erode their quality Gba1D409V/D409V synucleinopathy ( ) and ameliorate the associated of life (16, 17). Individuals harboring mutations in GBA1 also fi cognitive de cit. To probe this link further, we have now evalu- have a higher incidence of dementia that is correlated with the ated the efficacy of augmenting glucocerebrosidase activity in the D409V/D409V presence of neocortical accumulation of aggregates of α-synuclein NEUROSCIENCE CNS of symptomatic Gba1 mice and in a transgenic (18, 19). Indeed, mutations in GBA1 are now recognized as an mouse model overexpressing A53T α-synuclein. Adeno-associated independent risk factor for development of cognitive impairment virus-mediated expression of glucocerebrosidase in the CNS of Gba1D409V/D409V in PD patients (20). Another gene associated with an increased symptomatic mice completely corrected the aber- MAPT rant accumulation of the toxic lipid glucosylsphingosine and re- risk for dementia in PD is (21), the gene encoding the duced the levels of ubiquitin, tau, and proteinase K-resistant microtubule-associated protein tau, which helps maintain cyto- α α-synuclein aggregates. Importantly, hippocampal expression of skeletal organization and integrity. Tau-associated and -synu- D409V/D409V – glucocerebrosidase in Gba1 mice (starting at 4 or 12 clein associated pathology frequently occurs in patients with PD – mo of age) also reversed their cognitive impairment when exam- and LBD (22 24) although the relative roles of these proteins ined using a novel object recognition test. Correspondingly, over- are not well defined. Tau is more explicitly involved in Alzheimer’s expression of glucocerebrosidase in the CNS of A53T α-synuclein disease (25). mice reduced the levels of soluble α-synuclein, suggesting that We previously described a Gaucher-related synucleinopathy in increasing the glycosidase activity can modulate α-synuclein pro- mice with progressive CNS accumulation of proteinase K-resistant cessing and may modulate the progression of α-synucleinopathies. α-synuclein/ubiquitin aggregates reminiscent of LNs (10). These Hence, increasing glucocerebrosidase activity in the CNS repre- mice also have high CNS levels of the neurotoxin glucosyl- sents a potential therapeutic strategy for GBA1-related and non- sphingosine (GlcSph) and a hippocampal memory deficit. We GBA1–associated synucleinopathies, including PD. showed these biochemical and behavioral aberrations to be ameliorated by CNS administration into presymptomatic animals lysosomal storage diseases | mouse models | MAPT | memory defect of a recombinant adeno-associated viral (AAV) vector encoding human glucocerebrosidase. The present study further character- utations in the gene for glucocerebrosidase (GBA1) present izes the pathological features in this Gaucher-associated synu- Mthe highest genetic risk factor for developing synucleino- cleinopathy model, adding increased protein tau and demon- pathies such as Parkinson disease (PD) and dementia with Lewy strating cognitive improvement and moderation of CNS pathology bodies (DLB) (1–5). The central nervous system (CNS) of Gaucher when glucocerebrosidase was administered at a clinically relevant patients and carriers who present with parkinsonism and dementia postsymptomatic stage. Finally, to further probe the glucocere- harbor deposits of α-synuclein–positive Lewy bodies (LBs) and brosidase/α-synuclein relationship, the effect of the lysosomal Lewy neurites (LNs) in hippocampal neurons and their processes hydrolase on α-synuclein levels in the A53T α-synuclein mouse was resembling those noted in patients with classical PD and DLB (6, evaluated. 7). Aspects of these characteristics have also been noted in the CNS of several mouse models of neuropathic and nonneuropathic – Gaucher disease (8 10). Consequently, a causal relationship has Author contributions: S.P.S., S.H.C., and L.S.S. designed research; S.P.S., J.C., C.V., M.C., T.J.T., been suggested between the loss of glucocerebrosidase activity or C.M.T., J.B., L.S., M.A.P., J.C.D., and W.H.Y. performed research; S.P.S., J.C., C.V., M.C., W.H.Y., the lysosomal accumulation of undegraded metabolites and the R.L.S., and L.S.S. analyzed data; and S.P.S., R.L.S., S.H.C., and L.S.S. wrote the paper. development of PD and DLB. A more direct link between glu- The authors declare no conflict of interest. cocerebrosidase activity and α-synuclein metabolism has been Freely available online through the PNAS open access option. highlighted by studies of Gaucher cells and mice indicating that See Commentary on page 3214. a reduction in glucocerebrosidase activity by pharmacological or 1To whom correspondence may be addressed. E-mail: [email protected] genetic interventions resulted in increased levels of α-synuclein or [email protected]. – aggregates (9 12). Moreover, a decrease in glucocerebrosidase This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. activity has been noted in cerebrospinal fluid (CSF) and brain 1073/pnas.1220464110/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1220464110 PNAS | February 26, 2013 | vol. 110 | no. 9 | 3537–3542 Downloaded by guest on September 29, 2021 Results the blots with the Tau-5 antibody that recognizes all tau species revealed that the overall levels of the protein were not different CNS of a Mouse Model of Gaucher Disease Exhibits Accumulation of D409V/D409V Tau Aggregates. Accumulation of α-synuclein and tau inclusions between Gba1 and wild-type mice (Fig. 1C), nor were with resultant dementia are the hallmarks of a number of neu- differences in the extent of staining observed between controls Gba1D409V/D409V rodegenerative diseases, including PD and DLB (22, 25, 26). We and age-matched mice when the blots were probed C have reported that a mouse model of Gaucher disease har- with AT180 or AT270 antibodies (Fig. 1 ). However, AT8 boring a single point mutation in the murine Gba1 locus staining, which detects phosphorylation on Ser-202 and Thr-205, D409V/D409V fi (Gba1 ) exhibits progressive, marked accumulation was modestly but signi cantly increased in the lysates of Gba1D409V/D409V ± n = of α-synuclein/ubiquitin aggregates in the CNS and a measurable mice (1.3 0.1 compared with wild-type, 6, P < C deficit in hippocampal memory (10). To determine whether mu- 0.05; Fig. 1 ). This increased phosphorylation on Ser-202 tations in Gba1 with resultant loss of glucocerebrosidase activity and Thr-205, coupled with the progressive accumulation of the tau aggregates (in addition to α-synuclein), indicates that the also promote the accumulation of tau in the CNS, brain sections D409V/D409V D409V/D409V Gba1 of 12-mo-old Gba1 mice were examined immunohis- CNS of mice recapitulates pathological features tochemically with a specific anti-tau antibody. Marked punctate in PD and DLB patients. staining was noted primarily in the hippocampal regions (Fig. 1A), Administration of Glucocerebrosidase into the Hippocampus Re- although immunoreactivity was also observed in other areas, in- verses the Biochemical and Memory Aberrations of Postsymptomatic cluding cerebral cortex and cerebellum. The onset and rate of ac- D409V/D409V D409V/D409V Gba1 Mice. To determine whether reconstitution of the cumulation of the tau aggregates in the brains of Gba1 CNS with recombinant glucocerebrosidase can correct the bio- mice were determined as well. At 2 mo of age, tau immunore- fi Gba1D409V/D409V chemical aberrations and memory de cits of symptomatic activity in mice was not different from that in Gba1D409V/D409V A B mice, a recombinant self-complementary AAV wild-type controls (Fig. 1 and ). However, the level of tau – Gba1D409V/D409V fi vector (serotype 1) encoding human glucocerebrosidase
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