How does C9orf72 expansion impact protein degradation pathways in FTLD and ALS? скачать в хорошем качестве

How does C9orf72 expansion impact protein degradation pathways in FTLD and ALS?

Annakaisa Haapasalo, PhD, University of Eastern Finland, Joensuu, Finland, discusses her group’s work investigating the impact of C9orf72 hexanucleotide repeat expansion (HRE) expression on protein degradation pathways. C9orf72 HRE is the most common genetic cause underlying frontotemporal lobar degeneration (FLTD) and amyotrophic lateral sclerosis (ALS). While C9orf72 HRE contributes to disease pathogenesis through reduced C9orf72 levels, it also leads to the production of RNA foci and dipeptide repeat (DPR) proteins. To understand the role of these various pathogenic mechanisms, HRE-expressing cell models were generated. Analyses revealed that while the cells produced RNA foci and DPR proteins, these hallmarks did not cause changes in protein degradation pathways. However, knockdown of the C9orf72 led to impaired autophagy, suggesting that it is the loss-of-function mechanisms that lead to dysfunctional protein degradation. Dr Haapasalo discusses ongoing work to look at these pathways in human cells. This interview took place at the Harvard European Alumni Training Network (HEAT-Net) 2021 meeting.