Proteins Containing Expanded Polyglutamine Tracts and Neurodegenerative Disease

Abstract

Several hereditary neurological and neuromuscular diseases are caused by an abnormal expansion of trinucleotide repeats. To date, there have been ten of these trinucleotide repeat disorders associated with an expansion of the codon CAG encoding glutamine (Q). For these polyglutamine (polyQ) diseases, there is a critical threshold length of the CAG repeat required for disease, and further expansion beyond this threshold is correlated with age of onset and symptom severity. PolyQ expansion in the translated proteins promotes their self-assembly into a variety of oligomeric and fibrillar aggregate species that accumulate into the hallmark proteinaceous inclusion bodies associated with each disease. Here, we review aggregation mechanisms of proteins with expanded polyQ-tracts, structural consequences of expanded polyQ ranging from monomers to fibrillar aggregates, the impact of protein context and post translational modifications on aggregation, and a potential role for lipids membranes in aggregation. As the pathogenic mechanisms that underlie these disorders are often classified as either a gain of toxic function or loss of normal protein function, some toxic mechanisms associated with mutant polyQ tracts will also be discussed.

Biocompatible Inhibitor Based on Chitosan and Amphiphilic Peptide against Mutant Huntingtin Toxicity

“…Within these cases, HD is an autosomal dominantly inherited neurodegenerative disease caused by an expansion of the CAG trinucleotide repeats in the gene Huntingtin (HTT), which encodes a mutant HTT (mHtt) protein containing a prolonged polyglutamine (polyQ) stretch . The fragmentation of Htt is expected to be a key early step in the pathogenesis of HD .…”

A General Strategy to Access Structural Information at Atomic Resolution in Polyglutamine Homorepeats

“…Moreover, poly‐Q expansions form the basis of at least ten neurodegenerative disorders, including Huntington's Disease (HD), Kennedy's disease, and several ataxias 6, 7. HD is the most abundant and most well studied poly‐Q‐related disorder.…”

“…HD is the most abundant and most well studied poly‐Q‐related disorder. The causative agent of this deadly neurodegenerative pathology is the huntingtin protein (htt) 4, 7. Although full‐length htt has more than 3000 residues, the first exon (exon1; Figure 1 a), which contains the poly‐Q tract, is sufficient to replicate much of the pathology in cell and animal models 8.…”

“…Although full‐length htt has more than 3000 residues, the first exon (exon1; Figure 1 a), which contains the poly‐Q tract, is sufficient to replicate much of the pathology in cell and animal models 8. Importantly, only individuals with more than 35 consecutive glutamines (pathological threshold) develop HD symptoms, and disease onset and severity are correlated to the length of the poly‐Q expansion 7. All poly‐Q‐related diseases present similar pathological thresholds, thus suggesting a common amyloidogenic mechanism 9…”

FipoQ/FBXO33, a Cullin‐1‐based ubiquitin ligase complex component modulates ubiquitination and solubility of polyglutamine disease protein

“…Such expansion results in the production of an expanded polyQ tract in the disease proteins (Adegbuyiro et al . ). To date, nine diseases, including Huntington's disease, several types of spinocerebellar ataxias (SCAs) such as SCA3, dentatorubral‐pallidoluysian atrophy, and spinal and bulbar muscular atrophy have been reported to be caused by such CAG trinucleotide expansion mechanism (Paulson et al .…”