Polyglutamine tracts regulate beclin 1-dependent autophagy

Abstract

Nine neurodegenerative diseases are caused by expanded polyglutamine (polyQ) tracts in different proteins, like huntingtin in Huntington’s disease (HD) and ataxin-3 in spinocerebellar ataxia type 3 (SCA3)1, 2. Age-at-onset decreases with increasing polyglutamine length in these proteins and the normal length is also polymorphic3. PolyQ expansions drive pathogenesis in these diseases, as isolated polyQ tracts are toxic, and an N-terminal huntingtin fragment comprising exon 1, which occurs in vivo due to alternative splicing4, causes toxicity. While such mutant proteins are aggregate-prone5, toxicity is also associated with soluble forms of the proteins6. The function of the polyQ tracts in many normal/wild-type cytoplasmic proteins is unclear. One such protein is the deubiquitinating enzyme ataxin 37, 8, which is widely expressed in the brain9, 10. Here we show that the polyQ domain in wild-type ataxin-3 enables its interaction with beclin 1, a key autophagy initiator11. This interaction allows the deubiquitinase activity of ataxin-3 to protect beclin 1 from proteasome-mediated degradation and thus enables autophagy. Starvation-induced autophagy, which is regulated by beclin 1, was particularly inhibited in ataxin-3-depleted human cell-lines, primary neurons and in-vivo. This activity of ataxin-3 and its interaction with beclin 1 mediated by its polyQ domain was competed by other soluble proteins with polyQ tracts in a length-dependent fashion. This resulted in impaired starvation-induced autophagy in cells expressing mutant huntingtin exon 1, which was also recapitulated in the brain of HD mouse model and in patient cells. A similar phenomenon was also seen with other polyQ disease proteins, including mutant ataxin-3 itself. Our data thus describe a specific function for a wild-type polyQ tract which is abrogated by a competing longer polyQ mutation in a disease protein. This also reveals a deleterious function of such mutations distinct from their aggregation propensity.

Prolyl oligopeptidase inhibition reduces PolyQ aggregation and improves cell viability in cellular model of Huntington’s disease

“…However, Beclin1 was not significantly changed although KYP‐2047 increased it after lactacystin incubation (Figure G). Longer polyQ tracts are reported to increase the degradation of Beclin1 but this was not seen in our study. However, if KYP‐2047 can increase the levels of Beclin1 (as shown in Ref …”

The Missing Link in Polyglutamine Diseases

“…Importantly, this competition caused impairment of autophagy in cells expressing the toxic mutant huntingtin exon 1 in the brains of an HD transgenic mouse model as well as in HD patient‐derived cells. A similar phenomenon also was observed with other polyglutamine disease‐associated proteins, including mutant ataxin 3 itself . Because autophagy is crucial for clearance of misfolded proteins, including toxic polyglutamine expansions, competitive inhibition of autophagy by other polyglutamine‐containing proteins is likely to exacerbate neuronal dysfunction and pathology.…”

“…Because autophagy is crucial for clearance of misfolded proteins, including toxic polyglutamine expansions, competitive inhibition of autophagy by other polyglutamine‐containing proteins is likely to exacerbate neuronal dysfunction and pathology. The study by Ashkenazi and colleagues thus identifies a novel link between the different polyglutamine diseases and provides further rationale for a more thorough assessment of genotype‐phenotype interaction effects among the different polyglutamine disorders. On the one hand, this could yield novel modifiers of onset and progression; and, on the other hand, this could identify common targets for gene‐based therapies, which may prove efficacious in several polyglutamine disorders.…”

A Co‐occurrence of Trinucleotide Repeat Disorders

“…Though OPMD is not a polyglutamine repeat disorder, CAG repeat size variations in polyglutamine disease‐associated genes can modulate one another's phenotype (eg, the age of onset of HD and several expanded CAG‐repeat associated Spinocerebellar ataxias) . CAG trinucleotide length variants have been shown to regulate the clearance of misfolded proteins via beclin 1‐dependent autophagy, providing a pathogenic mechanism for the interaction between polyglutamine disease associated genes (well summarized in an article from this journal) . We cannot exclude that the co‐occurrence of HD and OPMD in our patient is purely coincidental, but one may wonder if a similar pathological mechanism, as discussed above with polyglutamate repeat expansions, may be at play in non‐polyglutamine triplet disorders.…”