Proteins Containing Expanded Polyglutamine Tracts and Neurodegenerative Disease.
Several hereditary neurological and neuromuscular diseases are caused by an abnormal expansion of trinucleotide repeats. To date, there have been 10 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 lipid 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.
The C. Eugene Bennett Department of Chemistry, 217 Clark Hall, West Virginia University , Morgantown, West Virginia 26506, United States.
Adewale
A
Adegbuyiro
The C. Eugene Bennett Department of Chemistry, 217 Clark Hall, West Virginia University , Morgantown, West Virginia 26506, United States.
Faezeh
F
Sedighi
The C. Eugene Bennett Department of Chemistry, 217 Clark Hall, West Virginia University , Morgantown, West Virginia 26506, United States.
Albert W
AW
Pilkington
The C. Eugene Bennett Department of Chemistry, 217 Clark Hall, West Virginia University , Morgantown, West Virginia 26506, United States.
Sharon
S
Groover
The C. Eugene Bennett Department of Chemistry, 217 Clark Hall, West Virginia University , Morgantown, West Virginia 26506, United States.|Blanchette Rockefeller Neurosciences Institute, Robert C. Byrd Health Sciences Center, P.O. Box 9304, West Virginia University , Morgantown, West Virginia 26506, United States.|NanoSAFE, P.O. Box 6223, West Virginia University , Morgantown, West Virginia 26506, United States.
Justin
http://orcid.org/0000-0002-5262-1867
J
Legleiter
D000818:Animals; D006801:Humans; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry*; D011499:Protein Processing, Post-Translational; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*
D010455:Peptides; D011506:Proteins; C097188:polyglutamine