Autophagy Genes Protect Against Disease Caused by Polyglutamine Expansion Proteins inCaenorhabditis elegans

Abstract

Previously published online a an Autophagy E-publication: http://www.landesbioscience.com/journals/autophagy/abstract.php?id=3528 KEY WORDSautophagy, polyQ proteins, neurodegeneration, C. elegans, muscle disease ACKNOWLEDGEMENTSThis work was supported by NIH R01grants CA109618 to B. L and NS40048 to A.C.H. We thank Christopher Gilpin and Tom Januszewski for assistance with electron microscopy; Richard Morimoto for providing critical reagents; and Michael Nonet for helpful advice. Research Paper Autophagy Genes Protect Against Disease Caused by Polyglutamine Expansion Proteins in Caenorhabditis elegans ABSTRACTExpanded polyglutamine (polyQ) proteins aggregate intracellularly in Huntington's disease and other neurodegenerative disorders. The lysosomal degradation pathway, autophagy, is known to promote clearance of polyQ protein aggregates in cultured cells. Moreover, basal autophagy in neuronal cells in mice prevents neurodegeneration by suppressing the accumulation of abnormal intracellular proteins. However, it is not yet known whether autophagy genes play a role in vivo in protecting against disease caused by mutant aggregate-prone, expanded polyQ proteins. To examine this question, we used two models of polyQ-induced toxicity in C. elegans, including the expression of polyQ40 aggregates in muscle and the expression of a human huntingtin disease fragment containing a polyQ tract of 150 residues (Htn-Q150) in ASH sensory neurons. Here, we show that genetic inactivation of autophagy genes accelerates the accumulation of polyQ40 aggregates in C. elegans muscle cells and exacerbates polyQ40-induced muscle dysfunction. Autophagy gene inactivation also increases the accumulation of Htn-Q150 aggregates in C. elegans ASH sensory neurons and results in enhanced neurodegeneration. These data provide in vivo genetic evidence that autophagy genes suppress the accumulation of polyQ aggregates and protect cells from disease caused by polyQ toxicity.

Decreased Insulin-Receptor Signaling Promotes the Autophagic Degradation of β-Amyloid Peptide inC. elegans

“…[77][78][79] In several aggregating-protein disease models, autophagy is implicated in degrading or preventing the formation of protein inclusions. 20,[80][81][82][83] We do not have evidence that the intracellular Aβ-deposits observed in our model 32 are the targeted cargo of autophagosomes (at least not in their entirety) because they are generally much larger than even the largest observed autophagosomes. This interpretation agrees with reports that polyglutamine and polyalanine protein inclusions are larger than autophagosomes and thus are incompatible as their cargo.…”

Omi/HtrA2 is a positive regulator of autophagy that facilitates the degradation of mutant proteins involved in neurodegenerative diseases

“…35 This finding was subsequently reported in Huntington's disease (HD) and other polyQ diseases, as well as in certain lysosomal storage disorders. 36,37 More persuasive evidence comes from autophagy-deficient animals, in which the conditional KO of ATG5 in the central nervous system results in neurodegeneration. 15 A broad array of age-related neurodegenerative diseases is characterized by the accumulation and deposition of misfolded proteins in affected brains, including AD, PD and the polyQ diseases.…”

Autophagy: for better or for worse

“…Indeed, environmental conditions or use of agents that promote the induction of autophagy have been shown to improve cellular fitness and survival [161]. In C. elegans and D. melanogaster, for example, caloric restriction (not involving malnutrition) enhances autophagic activity and increases the mean lifespan [162,163]. In addition, other autophagy-promoting treatments, e.g., rapamycin, resveratrol and spermidine, enhance cell survival, fitness and/or lifespan.…”

“…Therefore, autophagy can prevent the emergence of neurodegenerative diseases. Indeed, autophagy protects against aggregation-prone mutant proteins in spinocerebellar ataxia, mutated forms of α-synuclein in Parkinson's disease, mutant Huntingtin in Huntington's disease, tau mutants that cause frontotemporal dementia, pathogenic intraneuronal amyloid beta in Alzheimer disease brain and polyglucosan inclusion bodies in Lafora disease [162,196,[198][199][200][201][202]. Interestingly, most of these neurodegenerative diseases are associated with decreased Beclin-1 levels, which might account for the impaired autophagic clearance.…”