Abstract
SummaryHuntington’s disease is caused by an abnormally long polyglutamine tract in the huntingtin protein. This leads to the generation and deposition of N-terminal exon1 fragments of the protein in intracellular aggregates. We combined electron tomography and quantitative fluorescence microscopy to analyze the structural and material properties of huntingtin exon1 assemblies in mammalian cells, in yeast, and in vitro. We found that huntingtin exon1 proteins can form reversible liquid-like assemblies, a process driven by huntingtin’s polyQ tract and proline-rich region. In cells and in vitro, the liquid-like assemblies converted to solid-like assemblies with a fibrillar structure. Intracellular phase transitions of polyglutamine proteins could play a role in initiating irreversible pathological aggregation.
Highlights
Huntington’s disease (HD) is an incurable neurodegenerative disease, caused by a polyglutamine tract expansion in the huntingtin (HTT) protein (Bates et al, 2015)
Loss of HTT function may partly account for HD pathogenesis, it is known that small N-terminal, so called ‘‘exon1’’ fragments of HTT (HTTex1), generated by aberrant splicing (Sathasivam et al, 2013) are key mediators of toxicity
We will refer to these proteins as 25, 43, or 97QP-GFP, where the number indicates the polyQ length (e.g., 97Q) and the P indicates the C-terminal proline-rich region of HTTex1 (Figure 1A)
Summary
Huntington’s disease (HD) is an incurable neurodegenerative disease, caused by a polyglutamine (polyQ) tract expansion in the huntingtin (HTT) protein (Bates et al, 2015). Expression of HTTex proteins with expanded polyQ tracts causes HD-like symptoms in mice (Mangiarini et al, 1996) and is associated with toxicity in a range of other organisms, including yeast (Faber et al, 1999; Jackson et al, 1998; Meriin et al, 2002). HTTex is highly aggregation prone and is a major constituent of fibrillar aggregates found in the brains of HD patients (DiFiglia et al, 1997; Schilling et al, 2007). Such protein aggregates are a common feature of neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS) (Dugger and Dickson, 2017). Despite a clear link between HTTex aggregation and toxicity, little is known about the aggregation mechanism in cells
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
