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The molecular pathogenesis of polyglutamine diseases

A European study investigated the molecular mechanism underlying the pathogenesis of a neurodegenerative disorder. Their results have opened up novel therapeutic avenues for diseases such as spinal and bulbar muscular atrophy (SBMA).

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SBMA is a neurodegenerative disorder characterised by the loss of lower motor neurons that leads to progressive muscle weakness and atrophy. SBMA is a sex-specific disease, with full disease manifestations occurring only in males. At the molecular level, it is caused by repetition of CAG triplet(s) in the gene of the androgen receptor (AR), the receptor for the male hormones. When the gene is translated into the protein, the result is a polyglutamine tract. Upon androgen binding, AR translocates to the nucleus where it binds to androgen-responsive elements (ARE) and regulates the expression of androgen-responsive genes. However, the mechanism through which polyQ expansion in the AR causes motor neuron degeneration is currently unknown. To address this, scientists on the EU-funded POLYQ/AR (Polyglutamine diseases: Impact of protein and cell context on neurotoxicity) project proposed to study native protein function as a critical component to disease pathogenesis. The hypothesis was that the polyQ/AR-mediated neurotoxicity was a result of aberrant protein-protein interactions and cell context. Researchers unveiled at the post-translational level a phosphorylation of specific residues in the disease protein that affected its toxicity. In particular, activation of protein kinase A (PKA) modified the phosphorylation state of the mutant AR and protectively caused cell death. In another part of the project, they explored the involvement of the Forkhead transcription factor FOXO in polyQ-AR toxicity given its role in muscle atrophy. Their results indicated that FOXO was aberrantly activated in SBMA muscle and IGF-1/Akt signalling promoted neuronal survival through inhibition of FOXO. Taken together, the findings of the POLYQ/AR project point towards important modifiers of polyQ-AR toxicity. PKA and FOXO could function as therapeutic targets for SBMA and their modulation could provide novel treatment strategies for this debilitating disorder.


Polyglutamine disease, spinal and bulbar muscular atrophy, AR, toxicity, PKA, FOXO

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