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A hallmark of age-related neurodegenerative diseases is the presence of highly stable protein aggregates, also known as amyloid fibres. As these fibres are strongly associated with disease, it is thought that clearance of these fibres could delay or prevent disease progression. In this issue of The EMBO Journal, Beton et al unravel how the Hsc70/DNAJB1/Apg2 disaggregase machinery disassembles amyloid fibres, using α-synuclein fibrils implicated in Parkinson's Disease as a model substrate., (© 2022 The Authors.)

A loss of the checkpoint kinase ataxia telangiectasia mutated (ATM) leads to impairments in the DNA damage response, and in humans causes cerebellar neurodegeneration, and an increased risk of cancer. A loss of ATM is also associated with increased protein aggregation. The relevance and characteristics of this aggregation are still incompletely understood. Moreover, it is unclear to what extent other genotoxic conditions can trigger protein aggregation as well. Here, we show that targeting ATM, but also ATR or DNA topoisomerases, results in the widespread aggregation of a metastable, disease-associated subfraction of the proteome. Aggregation-prone model substrates, including Huntingtin exon 1 containing an expanded polyglutamine repeat, aggregate faster under these conditions. This increased aggregation results from an overload of chaperone systems, which lowers the cell-intrinsic threshold for proteins to aggregate. In line with this, we find that inhibition of the HSP70 chaperone system further exacerbates the increased protein aggregation. Moreover, we identify the molecular chaperone HSPB5 as a cell-specific suppressor of it. Our findings reveal that various genotoxic conditions trigger widespread protein aggregation in a manner that is highly reminiscent of the aggregation occurring in situations of proteotoxic stress and in proteinopathies., Competing Interests: WH, SD, Jv, RM, MM, GF, EG, DC, MO, LD, HS, Mv, SC, LB, JL, HK, SB No competing interests declared, (© 2022, Huiting et al.)