Polyglutamine Diseases: Where does Toxicity Come from? What is Toxicity? Where are We Going?

Abstract

Although the genetic basis of polyglutamine diseases has been recognized for 20 years, their molecular basis is still unclear. We have no therapeutic strategies for these intractable neurodegenerative disorders. To adequately treat patients, we must clarify the molecular basis of polyglutamine diseases. Three main issues address their molecular pathogenesis: whether the specific structure of expanded polyglutamine diseases results in cellular toxicity; what type of dysfunction causes them; and how the toxic structure causes dysfunction, that is, the link between structure and dysfunction. For structures, expanded polyglutamine proteins undergo transformation from monomers to oligomers and inclusions. One can hypothesize that one of these structures might cause the polyglutamine disease. Although the expanded polyglutamine protein is toxic, it does not explain the selective vulnerability of specific neurons in each polyglutamine disease. The normal function of each protein, including protein-protein interaction and modification, might also be crucial for pathogenesis. For dysfunction, various molecular mechanisms have been proposed, including dysregulation of transcription, impairment of the ubiquitin-proteasome system, mitochondrial dysfunction, dysregulation of intracellular Ca(2+) homeostasis, impairment of axonal transport and genotoxic stress. These hypotheses might correlate with each other. In addition, the disease pathogenesis of might not be exclusive to one particular structure or dysfunction. To develop a therapeutic strategy for patients with polyglutamine disease, identifying the most toxic structure and the earliest event in the pathogenesis is important. We review the current understanding of the toxic structure and dysfunction by expanded polyglutamine proteins and suggest directions for future studies of polyglutamine diseases.

Overexpression of Cystathionine γ-Lyase Suppresses Detrimental Effects of Spinocerebellar Ataxia Type 3

“…Pauline M Snijder, 1* Madina Baratashvili, 2* Nicola A Grzeschik, 2 Henri G D Leuvenink, 3 Lucas Kuijpers, 2 Sippie Huitema, 1 Onno Schaap, 2 Ben N G Giepmans, 4 Jeroen Kuipers, 4 Jan Lj Miljkovic, 5 Aleksandra Mitrovic, 6 Eelke M Bos, 1 Csaba Szabó, 7 Harm H Kampinga, 2 Pascale F Dijkers, 2 Wilfred F A den Dunnen, 1 Milos R Filipovic, 5 Harry van Goor, 1* and Ody C M Sibon 2*…”

“…The pathophysiological sequel of neurodegeneration in SCA3 is not fully understood, although proteotoxic stress, transcriptional dysregulation, mitochondrial dysfunction, oxidative stress and inflammation have been implicated (5)(6)(7). To date, there are no disease-modifying treatments for polyQ diseases such as SCA3.…”

Huntington disease arises from a combinatory toxicity of polyglutamine and copper binding

“…Whether these disorders share the same pathogenic mechanism linking to polyQ has caused considerable controversy (reviewed in ref. 34). Although we found copper modulates the disease progression of HD flies, altering the expression of copper transporters fails to affect the phenotypes of polyQ flies, including the survival and eye phenotypes.…”

Machado-Joseph Disease / Spinocerebellar Ataxia Type 3

“…Mutant ataxin-3 is widely expressed in the brain (Paulson et al, 1997a), even in areas with no significant neuronal degeneration. Thus, the normal function of ataxin-3 or interactions with other proteins in each neuronal subpopulation might explain its selective toxicity (Takahashi et al, 2010). Normal ataxin-3 is found in nuclear inclusions of different polyglutamine diseases, particularly in spinocerebellar ataxia type 1 -SCA1, SCA2, Dentatorubralpallidoluysian atrophy, ) and in neuronal intranuclear hyaline inclusion disease .…”