TY - JOUR
T1 - Polyglutamine Repeats in Neurodegenerative Diseases
AU - Lieberman, Andrew P.
AU - Shakkottai, Vikram G.
AU - Albin, Roger L.
N1 - Funding Information:
Work in the authors’ laboratories is supported by the US National Institutes of Health (grants R01 NS055746 and R21 NS101030 to A.P.L., R01 NS085054 to V.G.S., P50 NS091856 and R21 NS088302 to R.L.A.) and the Muscular Dystrophy Association (MDA 513702 to A.P.L.).
Publisher Copyright:
© 2019 by Annual Reviews. All rights reserved.
PY - 2019
Y1 - 2019
N2 - Among the age-dependent protein aggregation disorders, nine neurodegenerative diseases are caused by expansions of CAG repeats encoding polyglutamine (polyQ) tracts. We review the clinical, pathological, and biological features of these inherited disorders. We discuss insights into pathogenesis gleaned from studies of model systems and patients, highlighting work that informs efforts to develop effective therapies. An important conclusion from these analyses is that expanded CAG/polyQ domains are the primary drivers of neurodegeneration, with the biology of carrier proteins influencing disease-specific manifestations. Additionally, it has become apparent that CAG/polyQ repeat expansions produce neurodegeneration via multiple downstream mechanisms, involving both gain- and loss-of-function effects. This conclusion indicates that the likelihood of developing effective therapies targeting single nodes is reduced. The evaluation of treatments for premanifest disease will likely require new investigational approaches. We highlight the opportunities and challenges underlying ongoing work and provide recommendations related to the development of symptomatic and disease-modifying therapies and biomarkers that could inform future research.
AB - Among the age-dependent protein aggregation disorders, nine neurodegenerative diseases are caused by expansions of CAG repeats encoding polyglutamine (polyQ) tracts. We review the clinical, pathological, and biological features of these inherited disorders. We discuss insights into pathogenesis gleaned from studies of model systems and patients, highlighting work that informs efforts to develop effective therapies. An important conclusion from these analyses is that expanded CAG/polyQ domains are the primary drivers of neurodegeneration, with the biology of carrier proteins influencing disease-specific manifestations. Additionally, it has become apparent that CAG/polyQ repeat expansions produce neurodegeneration via multiple downstream mechanisms, involving both gain- and loss-of-function effects. This conclusion indicates that the likelihood of developing effective therapies targeting single nodes is reduced. The evaluation of treatments for premanifest disease will likely require new investigational approaches. We highlight the opportunities and challenges underlying ongoing work and provide recommendations related to the development of symptomatic and disease-modifying therapies and biomarkers that could inform future research.
KW - polyglutamine, neurodegeneration, trinucleotide repeat disorders, Huntington's disease, spinal and bulbar muscular atrophy, spinocerebellar ataxia
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U2 - 10.1146/annurev-pathmechdis-012418-012857
DO - 10.1146/annurev-pathmechdis-012418-012857
M3 - Review article
C2 - 30089230
AN - SCOPUS:85059899824
SN - 1553-4006
VL - 14
SP - 1
EP - 27
JO - Annual Review of Pathology: Mechanisms of Disease
JF - Annual Review of Pathology: Mechanisms of Disease
ER -