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Striatal Vulnerability in Huntington's Disease: Neuroprotection Versus brain sciences Review Striatal Vulnerability in Huntington’s Disease: Neuroprotection Versus Neurotoxicity Ryoma Morigaki 1,2,3 and Satoshi Goto 1,2,* 1 Parkinson’s Disease and Dystonia Research Center, Tokushima University Hospital, Tokushima University, Tokushima 770-8503, Japan; [email protected] 2 Department of Neurodegenerative Disorders Research, Institute of Biomedical Sciences, Graduate School of Medical Sciences, Tokushima University, Tokushima 770-8503, Japan 3 Department of Neurosurgery, Institute of Biomedical Sciences, Graduate School of Medical Sciences, Tokushima University, Tokushima 770-8503, Japan * Correspondence: [email protected]; Tel.: +81-88-633-7206; Fax: +81-88-633-7208 Academic Editor: Edamakanti Chandrakanth Reddy Received: 2 May 2017; Accepted: 3 June 2017; Published: 7 June 2017 Abstract: Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease caused by the expansion of a CAG trinucleotide repeat encoding an abnormally long polyglutamine tract (PolyQ) in the huntingtin (Htt) protein. In HD, striking neuropathological changes occur in the striatum, including loss of medium spiny neurons and parvalbumin-expressing interneurons accompanied by neurodegeneration of the striosome and matrix compartments, leading to progressive impairment of reasoning, walking and speaking abilities. The precise cause of striatal pathology in HD is still unknown; however, accumulating clinical and experimental evidence suggests multiple plausible pathophysiological mechanisms underlying striatal neurodegeneration in HD. Here, we review and discuss the characteristic neurodegenerative patterns observed in the striatum of HD patients and consider the role of various huntingtin-related and striatum-enriched proteins in neurotoxicity and neuroprotection. Keywords: Huntington’s disease; huntingtin; striatum; medium spiny neuron; pathophysiology; striosome; matrix 1. Introduction Huntington’s disease (HD) is an autosomal dominantly inherited neurodegenerative disorder characterized by the late onset of gradually worsening motor, cognitive, and psychiatric disturbances [1]. At present, HD is largely untreatable and the mean survival time of individuals with HD is 17–20 years after symptom onset [2]. In HD, a mutation of the protein huntingtin (Htt), which involves the expansion of a cytosine-adenine-guanine (CAG) repeat encoding an extended glutamine tract (PolyQ), causes transcriptional dysregulation (Figure1) resulting in multiple cellular dysfunctions such as intracellular signaling pathway alterations, protein trafficking defects, synaptic transmission impairments, proteasome dysfunction, and mitochondrial alterations [3–5]. Htt is highly conserved among vertebrates and is expressed ubiquitously in the human body [6]. Its highest levels are found in the brain, where it is expressed in all neurons and glial cells [3]. Despite the ubiquitous expression of mutant Htt (mHtt) throughout the brain, human pathology has shown that degeneration is specific to certain neuronal subpopulations affecting the striatum and, to a lesser extent, the cerebral cortex in patients with HD [4]. In the striatum, a differential involvement of striosome and matrix compartments has been reported in HD [5–12]. Moreover, ongoing neurodegeneration is preferentially found in medium spiny neurons (MSNs) and parvalbumin-expressing interneurons in the striatum [13–18]. These findings indicate that striatal cell type- and compartment-specific vulnerabilities may underlie the etiology Brain Sci. 2017, 7, 63; doi:10.3390/brainsci7060063 www.mdpi.com/journal/brainsci Brain Sci. 2017, 7, 63 2 of 24 Brain Sci. 2017, 7, 63 2 of 25 cell type‐ and compartment‐specific vulnerabilities may underlie the etiology of striatal pathology inof HD striatal [19]. pathology Here, we indiscuss HD [striatal19]. Here, cell wetype discuss‐ and compartment striatal cell type-‐specific and degeneration compartment-specific in HD as welldegeneration as neuroprotection in HD as well and as neurotoxicity neuroprotection associated and neurotoxicity with Htt‐ associatedrelated and with striatum Htt-related‐enriched and proteins.striatum-enriched proteins. FigureFigure 1. 1. AnAn example example of of transcriptional transcriptional dysregulation dysregulation by by mutant mutant Huntingtin Huntingtin protein. protein. ( (AA)) Wild Wild-type‐type HuntingtinHuntingtin interacts withwith CREB-binding CREB‐binding protein protein (CBP) (CBP) and and possibly possibly with with TATA TATA box binding box binding protein proteinassociated associated factor factor (TAF) (TAF) II 130 II and/or130 and/or TATA TATA box box binding binding protein protein (TBP). (TBP). HuntingtinHuntingtin promotes promotes transcriptiontranscription of of encephalin; encephalin; ( (BB)) Mutant Mutant Huntingtin Huntingtin binds binds CBP, CBP, TAF TAF II II 130 130 and and TBP TBP and and prevents prevents thesethese transcriptiontranscription factorsfactors from from recruitment. recruitment. P: phosphorylation,P: phosphorylation, TF: transcriptionTF: transcription factor, factor, CRE: cAMPCRE: cAMPresponse response element, element, CREB: CREB: cAMP cAMP response response element-binding element‐binding protein. protein. 2.2. Striatal Striatal Anatomy Anatomy InIn HD, HD, the the striatum striatum has has been been identified identified as as the the primarily affected structure, structure, which which undergoes undergoes severesevere degeneration. degeneration. As As a a core core structure structure of of basal ganglia circuits, the striatum integrates midbrain dopaminergicdopaminergic inputsinputs and and neocortical neocortical and thalamicand thalamic glutamatergic glutamatergic inputs, andinputs, then and sends then GABAergic sends GABAergicoutputs to itsoutputs target to nuclei, its target such nuclei, as the such globus as the pallidus globus pallidus and substantia and substantia nigra. Thenigra. striatum The striatum plays playsa critical a critical role inrole processing in processing information information related related to to motor motor function function and and reward- reward‐ andand goal-orientedgoal‐oriented behavior.behavior. To To facilitate the the understanding of of HD HD neuropathology, we we brieflybriefly review normal striatal anatomyanatomy (Figure (Figure 2).2). 2.1.2.1. Fundamental Fundamental Structure Structure Respectively,Respectively, MSNs MSNs (10–24 (10–24 μµmm in in diameter) and medium aspiny interneurons represent represent approximatelyapproximately 90%90% andand 10% 10% of of striatal striatal neurons neurons in rodents,in rodents, and approximatelyand approximately 75% and75% 25% and of 25% striatal of striatalneurons neurons in primates in primates [20,21]. The[20,21]. four The GABAergic four GABAergic interneuron interneuron subtypes subtypes found within found the within striatum the striatumexpress (1) express parvalbumin; (1) parvalbumin; (2) calretinin; (2) calretinin; (3) coexpressing (3) coexpressing nicotinamide nicotinamide adenine dinucleotide adenine dinucleotide phosphate phosphate(NADPH) diaphorase,(NADPH) nitricdiaphorase, oxide synthase nitric oxide (NOS), synthase neuropeptide (NOS), Y (NPY) neuropeptide and somatostatin; Y (NPY) and and (4) somatostatin;tyrosine hydroxylase and (TH)(4) expressingtyrosine interneuronshydroxylase [ 20(TH)–24]. Parvalbumin-positiveexpressing interneurons interneurons [20–24]. (i.e., Parvalbumin“fast-firing interneurons”)‐positive interneurons can block or(i.e., delay “fast the‐firing firing interneurons”) of more than 100 can MSNs block [22 or,25 delay]. NOS-containing the firing of moreinterneurons than 100 (i.e., MSNs “low-threshold [22,25]. NOS spike‐containing interneurons”) interneurons release (i.e., nitric “low oxide‐threshold (NO) via spike dopamine interneurons”) D1/D5 releasereceptor nitric (D1R/D oxide5R) activation(NO) via anddopamine influence D the1/D5 induction receptor of (D long-term1R/D5R) activation depression and (LTD) influence via the cyclic the inductionguanosine of monophosphate long‐term depression (cGMP) (LTD) pathway via [the26]. cyclic Large guanosine aspiny cholinergic monophosphate interneurons (cGMP) (21–45 pathwayµm in [26].diameter) Large representaspiny cholinergic 1%–2% of interneurons the total cell (21–45 population μm in in diameter) the human represent striatum 1%–2% [27]. Theof the cholinergic total cell populationinterneurons in play the a rolehuman in the striatum spatiotemporal [27]. The selection cholinergic of convergent interneurons inputs to play striatal a MSNsrole in [28 ].the spatiotemporal selection of convergent inputs to striatal MSNs [28]. Brain Sci. 2017, 7, 63 3 of 25 Brain Sci. 2017, 7, 63 3 of 24 FigureFigure 2. 2. StriatalStriatal structural structural anatomy anatomy and and functional functional circuitry circuitry model. model. (A ()A A) A human human striatum striatum section section immunostainedimmunostained with with anti anti-Met-enkephalin‐Met‐enkephalin antibody. antibody. (From (From Goto Goto et etal. al. (2015) (2015) with with permission) permission) [29]; [29 ]; (B()B )Low Low-power-magnified‐power‐magnified microscopic microscopic negative negative image image of of the the caudate caudate nucleus. nucleus. Asterisks Asterisks indicate indicate striosomesstriosomes (From (From Goto Goto et al.al. (2015) (2015) with with permission) permission) [29 ];[29]; (C) ( StriatumC) Striatum plays plays a central a central role of role multiple of multiplefeedback feedback and feedforward and feedforward regulations regulations
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