Glutamine Repeats and Neurodegeneration

Abstract

A growing number of neurodegenerative diseases have been found to result from the expansion of an unstable trinucleotide repeat. Over the past 6 years, researchers have focused on identifying the mechanism by which the expanded polyglutamine tract renders a protein toxic to a subset of vulnerable neurons. In this review, we summarize the clinicopathologic features of these disorders (spinobulbar muscular atrophy, Huntington disease, and the spinocerebellar ataxias, including dentatorubropallidoluysian atrophy), describe the genes involved and what is known about their products, and discuss the model systems that have lent insight into pathogenesis. The review concludes with a model for pathogenesis that illuminates the unifying features of these polyglutamine disorders. This model may prove relevant to other neurodegenerative disorders as well.

ER stress and neurodegenerative diseases

“…These disorders are characterized by selective neuronal death and accumulation of intracellular protein aggregates observed in cultured cells, transgenic animals and in human post-mortem brain tissue. 57 The significance of the polyQ expansions and ER stress and neurodegeneration D Lindholm et al protein deposits for disease pathophysiology remains unclear. It has been proposed that alterations in gene expression, changes in protein-protein interactions, dysfunctional mitochondrial and an impairment of the UPS contributed to the disease progression.…”

“…It has been proposed that alterations in gene expression, changes in protein-protein interactions, dysfunctional mitochondrial and an impairment of the UPS contributed to the disease progression. 57,58 It is a matter of debate whether the polyQ protein aggregates are deleterious for neurons or whether they preserve vital functions in the cell. 58 Mutant huntingtin can affect calcium metabolism in the cell and sensitize the IP3 receptors at the ER.…”

“…58 This was also observed in some, but not all mouse models of polyQ diseases. 57,58 ER stress is also triggered by the pathogenic SCA3 polyQ fragments, as shown by the activation of IRE1 and PERK and the induction of CHOP/Gadd153 and BiP/Grp78. This occurred after an impairment of proteasomes showing the interplay between the ER and the UPS.…”

Are amyloid diseases caused by protein aggregates that mimic bacterial pore-forming toxins?

“…Huntington's disease is the most prevalent of a group of purely genetic neurodegenerative movement disorders that are caused by expansions of naturally occurring polyglutamine (polyQ) tracts in several proteins (the normal function of these tracts is not known) (Zoghbi & Orr, 2000). The magnitude of the expansion is related to the age of onset of the disease, with large expansions causing juvenile onset disease.…”

Chapter 3 A Fluorescent Window Into Protein Folding and Aggregation in Cells

“…2A). Increasing the polyQ length beyond the threshold length of 35 consecutive glutamines characteristic of polyQ diseases (Ross and Poirier, 2004;Zoghbi and Orr, 2000) causes an increase in the bulkfluorescence signal, and reduces the time for onset of the rise in fluorescence. Furthermore, the plateau fluorescence increases in proportion to length of the polyQ tract (Fig.…”