Toward therapeutic targets for SCA3: Insight into the role of Machado–Joseph disease protein ataxin-3 in misfolded proteins clearance. (September 2015)

• Record Type: Journal Article
• Authors: Li, Xiaoling; Liu, Hongmei; Fischhaber, Paula L.; Tang, Tie-Shan
• Is Part Of: Progress in neurobiology. Volume 132(2015:Sep.)
• Page Start: 34
• Page End: 58
• Publication Date: 2015-09
• Subjects: Machado–Joseph disease -- Ataxin-3 -- Polyglutamine -- Deubiquitinase -- Misfolded protein clearance; 17-AAG 17-N-allylamino-17-demethoxygeldanamycin -- 17-DMAG 17-dimethylaminoethylamino-17-demethoxy-geldanamycin -- 3-NP 3-nitropropionic acid -- AD Alzheimer's disease -- ADAS-cog cognitive subscale of the Alzheimer's disease assessment scale -- ALA α-linolenic acid -- ALS amyotrophic lateral sclerosis -- AR androgen receptor -- ARA arachidonic acid -- Ataxin-3exp pathogenic form of ataxin-3 -- C14 cysteine residue 14 -- CCFS composite cerebellar functional score -- CDR clinical dementia rating -- CIBIC-plus clinician's interview-based impression of change scale which included caregiver-supplied information -- DHA docosahexaenoic acid -- DUB deubiquitinase -- EFA sessential fatty acids -- EPL ɛ-poly-l-lysine -- ERAD endoplasmic-reticulum-associated protein degradation -- FDA Food and Drug Administration -- HD Huntington's disease -- HSR heat shock response -- ICDs impulse-control disorders -- IP3 inositol-1, 4, 5-triphosphate -- LA linolenic acids -- LCPUFAs long-chain polyunsaturated fatty acids -- LID levodopa-induced dyskinesias -- LPL lysophospholipids -- MCI mild cognitive impairment -- MJD Machado–Joseph disease -- MMS Emini-mental state examination -- MPTP 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine -- NESSCA neurological examination score for spinocerebellar ataxia -- NF-YA nuclear factor-YA -- NPI neuropsychiatric inventory -- P/CD parkinsonism and cognitive decline -- PD Parkinson's disease -- polyQ polyglutamine -- PQC protein quality control -- RBANS repeatable battery for the assessment of neuropsychological status -- RDBPC randomized double blind placebo controlled -- SBMA spinal and bulbar muscular atrophy -- SCA3 spinocerebellar ataxia type 3 -- SCAFI spinocerebellar ataxia Functional Inde -- SDS sodium dodecyl sulfate -- SMA spinal muscular atrophy -- Ub ubiquitin -- UBA ubiquitin-associated domains -- UBL ubiquitin-like domain -- UIM ubiquitin interacting motifs -- UPS ubiquitin–proteasome systems -- VPA dodium valproate; Neurobiology -- Periodicals; Neurology -- Periodicals; Neurology -- Periodicals; Neurobiologie -- Périodiques; 612.8
• DOI: 10.1016/j.pneurobio.2015.06.004
• Languages: English
• ISSNs: 0301-0082

Abstract

Graphical abstract: Highlights: UIM domains and Josephin domain confer the ubiquitin trimming activity of ataxin-3. Ataxin-3 is actively involved in the clearance misfolded proteins. Pathogenic ataxin-3 impairs the misfolded protein clearance. Targeting misfolded protein clearance holds great therapeutic potential to treat SCA3. Abstract: Machado–Joseph disease (MJD, also known as spinocerebellar ataxia type 3, SCA3), an autosomal dominant neurological disorder, is caused by an abnormal expanded polyglutamine (polyQ) repeat in the ataxin-3 protein. The length of the expanded polyQ stretch correlates positively with the severity of the disease and inversely with the age at onset. To date, we cannot fully explain the mechanism underlying neurobiological abnormalities of this disease. Yet, accumulating reports have demonstrated the functions of ataxin-3 protein in the chaperone system, ubiquitin–proteasome system, and aggregation-autophagy, all of which suggest a role of ataxin-3 in the clearance of misfolded proteins. Notably, the SCA3 pathogenic form of ataxin-3 (ataxin-3 exp ) impairs the misfolded protein clearance via mechanisms that are either dependent or independent of its deubiquitinase (DUB) activity, resulting in the accumulation of misfolded proteins and the progressive loss of neurons in SCA3. Some drugs, which have been used as activators/inducers in the chaperone system, ubiquitin–proteasome system, and aggregation-autophagy, have been demonstrated to be efficacious in the relief of neurodegeneration diseases like Huntington's disease (HD), Parkinson's (PD), Alzheimer's (AD) as well as SCA3 in animal models and clinical trials, putting misfolded protein clearance on the list of potential therapeutic targets. Here, we undertake a comprehensive review of the progress in understanding the physiological functions of ataxin-3 in misfolded protein clearance and how the polyQ expansion impairs misfolded protein clearance. We then detail the preclinical studies targeting the elimination of misfolded proteins for SCA3 treatment. We close with future considerations for translating these pre-clinical results into therapies for SCA3 patients.