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Several neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis are characterized by protein aggregation, while an impaired DNA damage response (DDR) as in many genetic DNA repair disorders leads to pronounced neuropathological features. It remains unclear to what degree these cellular events interconnect with each other in the development of neurological diseases. This review highlights how the loss of protein homeostasis and genome instability influence one other. We will discuss studies that illustrate this connection. DNA damage contributes to many neurodegenerative diseases, as shown by an increased level of DNA damage in patients, possibly due to the effects of protein aggregates on chromatin, the sequestration of DNA repair proteins and novel putative DNA repair functions. Conversely, genome stability is also important for protein homeostasis. For example, gene copy number variations and the loss of key DDR components can lead to marked proteotoxic stress. An improved understanding of how protein homeostasis and genome stability are mechanistically connected is needed and promises to lead to the development of novel therapeutic interventions.<\/jats:p>","DOI":"10.1098\/rsob.200296","type":"journal-article","created":{"date-parts":[[2021,4,21]],"date-time":"2021-04-21T03:43:21Z","timestamp":1618976601000},"update-policy":"https:\/\/doi.org\/10.1098\/crossmark-policy","source":"Crossref","is-referenced-by-count":42,"title":["Genome instability and loss of protein homeostasis: converging paths to neurodegeneration?"],"prefix":"10.1098","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4209-0150","authenticated-orcid":true,"given":"Anna","family":"Ainslie","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences of Cells and Systems, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands"},{"name":"Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0371-512X","authenticated-orcid":true,"given":"Wouter","family":"Huiting","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences of Cells and Systems, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6538-2383","authenticated-orcid":true,"given":"Lara","family":"Barazzuol","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences of Cells and Systems, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands"},{"name":"Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1142-869X","authenticated-orcid":true,"given":"Steven","family":"Bergink","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences of Cells and Systems, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"175","published-online":{"date-parts":[[2021,4,21]]},"reference":[{"key":"e_1_3_6_2_2","unstructured":"United Nations Department of Economic and Social Affairs Population Division. 2019 World Population Prospects 2019 Online Edition. 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