Aggregation Formation in the Polyglutamine Diseases: Protection at a Cost?

Abstract

Mutant protein aggregation is a hallmark of many neurodegenerative diseases, including the polyglutamine disorders. Although the correlation between aggregation formation and disease pathology originally suggested that the visible inclusions seen in patient tissue might directly contribute to pathology, additional studies failed to confirm this hypothesis. Current opinion in the field of polyglutamine disease research now favors a model in which large inclusions are cytoprotective and smaller oligomers or misfolded monomers underlie pathogenesis. Nonetheless, therapies aimed at reducing or preventing aggregation show promise. This review outlines the debate about the role of aggregation in the polyglutamine diseases as it has unfolded in the literature and concludes with a brief discussion on the manipulation of aggregation formation and clearance mechanisms as a means of therapeutic intervention.

Poly(Q) Expansions in ATXN7 Affect Solubility but Not Activity of the SAGA Deubiquitinating Module

“…Aggregation of poly(Q) proteins is a hallmark of CAG expansion disorders (2). Aggregates associated with ATXN7-poly(Q) mutants also include transcriptional regulators, ubiquitin/proteasome proteins, cell death-associated proteins, chaperones, and ATXN7 protein partners (1).…”

“…pinocerebellar ataxia type 7 (SCA7) is one of nine polyglutamine [poly(Q)] expansion diseases associated with progressive neurodegeneration (1)(2)(3). SCA7 is caused by poly(Q) expansions within the N-terminal (NT) region of ATXN7.…”

“…SCA7 is caused by poly(Q) expansions within the N-terminal (NT) region of ATXN7. In unaffected individuals, ATXN7 contains 4 to 35 glutamine (Q) residues, whereas in SCA7 patients, ATXN7 contains from more than 36 to up to a few hundred poly(Q) repeats (2). The length of the poly(Q) expansion correlates inversely with the age of onset and the severity of the disease (4).…”

“…The length of the poly(Q) expansion correlates inversely with the age of onset and the severity of the disease (4). Although it is generally agreed that aggregation of the expanded glutamine tract plays a critical role in neurotoxicity, the exact molecular mechanism of toxicity remains unclear (2).…”

The aggregation and inheritance of damaged proteins determines cell fate during mitosis

“…8 This led to the theory that diffuse Htt is the more toxic conformation, and inclusion bodies protect the cell from death by sequestering diffuse Htt, 8 although this is still under debate. 9 So far, the toxicity of different conformations of Htt primarily has been studied in differentiated cells, as the symptoms of HD result from neuronal death. Cells capable of proliferation also are susceptible to damaged protein toxicity, and it is unclear whether the conformation of damaged proteins determines their toxicity.…”