Targeting protein aggregation in neurodegeneration – lessons from polyglutamine disorders

Abstract

Polyglutamine diseases, such as Huntington's disease, are among the most common inherited neurodegenerative disorders. They share salient clinical and pathological features with major sporadic neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and amyotropic lateral sclerosis. Over the last decade, protein aggregation has emerged as a common pathological hallmark in neurodegenerative diseases and has, therefore, attracted considerable attention as a likely shared therapeutic target. Because of their clearly defined molecular genetic basis, polyglutamine diseases have allowed researchers to dissect the relationship between neurodegeneration and protein aggregation. In this review, the authors discuss recent progress in understanding polyglutamine-mediated neurotoxicity, and discuss the most promising therapeutic strategies being developed in the polyglutamine diseases and related neurodegenerative disorders.

Proteasomes Cleave at Multiple Sites within Polyglutamine Tracts

“…Expansions that result in altered protein structure involve two amino acids, an alanine encoded by GCG and glutamine (Q) encoded by CAG (2,3). Both polyalanine and polyglutamine expansions lead to the formation of insoluble inclusions, usually nuclear, that often recruit chaperones, ubiquitin, proteasomes, and a variety of other proteins (4,5). Glutamine tract expansions occur in a disparate set of proteins with no common biochemical function, and the polyglutamine diseases, such as Huntington, Kennedy, and a number of ataxias, usually occur when the glutamine tract exceeds 35 residues in length (6).…”

Sodium dodecyl sulfate‐insoluble oligomers are involved in polyglutamine degeneration

“…Conversely, polyQ aggregates have also been reported to attenuate toxicity in vitro (16). To date, the pathogenic polyQ protein conformers are not well defined and still under investigation (15,(17)(18)(19).…”

Hydrogen Bond Surrogate‐Constrained Dynamic Antiparallel β‐Sheets

“…Therefore, the design of dynamic templates that mimic the random‐coil (non‐β‐sheet)⇄antiparallel β‐sheet transitions, represent the next level in this direction of chemical biology. Such dynamic templates are essential to augment our current understanding of their influence on several neurodegenerative diseases [20–24] …”