Molecular and clinical determinants of pathogenic protein aggregation: modulation of polyglutamine diseases by molecular chaperones

Correct protein folding is essential for life, but in the complex cellular environment proteins face many risks of misfolding and/or aggregating. Protein aggregation, especially of so-called amyloids, is a hallmark of many neurodegenerative diseases. Understanding how amyloids form, which factors influence onset and speed of aggregation, and how these processes can be inhibited is of immediate relevance to diseases such as Alzheimer’s, Parkinson’s, Huntington’s (HD), and spinocerebellar ataxias (SCAs). In HD and some SCAs, expansions of the DNA sequence CAG lead to aggregation-prone proteins with abnormally long polyglutamine (polyQ) tracts. This thesis sought to understand how genetic factors modulate polyQ aggregation and toxicity. Cells possess so-called molecular chaperones to assist correct protein folding and prevent aggregation, and we focused on the anti-aggregation properties of one special chaperone, namely DNAJB6, characterizing it as a powerful suppressor of amyloid aggregation. Our data show that polyQ molecules can partition into liquid-like “condensates” before aggregating into solid amyloids. DNAJB6 can co-condensate with these polyQ assemblies and block their transition to amyloids, largely independently of other protein degradation pathways that also deal with aggregates. We also investigated potential genetic modifiers of the age at onset (AO) of MJD/SCA3, which is driven by polyQ aggregation and toxicity, and uncovered a strong dependency of AO variability on geographical origin of the affected individual. DNAJB6 levels, however, were not related to AO. Yet, our data did generate more accurate models of AO prediction, which are crucial for genetic counseling and recruitment of at-risk individuals to clinical trials.