{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:51:32Z","timestamp":1791161492592,"version":"4.1.0"},"reference-count":121,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T00:00:00Z","timestamp":1773187200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Rising Star Brain Canada"},{"DOI":"10.13039\/501100021106","name":"Cermo-FC","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100021106","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012618","name":"Fondation Armand-Frappier","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100012618","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000156","name":"FRQS","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000156","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000038","name":"Natural Science and Engineering Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["CIHR-177940"],"award-info":[{"award-number":["CIHR-177940"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>A hexanucleotide (GGGGCC) repeat expansion in the C9orf72 gene represents the most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), resulting in reduced C9orf72 mRNA and protein expression. C9orf72 is highly expressed in the cerebellum, and growing evidence implicates C9orf72-associated cerebellar pathology across neurodegenerative disorders, including ALS\/FTD, yet the pathogenic mechanisms remain unresolved.<\/jats:p>\n                  <jats:p>Here, we demonstrate that in vivo C9orf72 loss of function leads to cerebellar atrophy, loss of GABAergic interneurons and depletion of Purkinje and granule cells. Additionally, we demonstrate that these cerebellar anomalies precede motor defects. Single-cell transcriptomics of the C9orf72 zebrafish brain revealed the downregulation of a purine biosynthetic gene, paics, in Purkinje cells.<\/jats:p>\n                  <jats:p>Furthermore, we demonstrate the reduced expression of PAICS in human post-mortem cerebellar sections and induced pluripotent stem cell-derived motor neurons from C9orf72 and sporadic ALS patients. Knockout of paics in zebrafish recapitulates cerebellar neuronal loss, neuromuscular junction disruption, motor impairment and widespread DNA damage and repair defects, including suppression of key DNA repair pathways.<\/jats:p>\n                  <jats:p>Restoring paics expression in C9orf72 zebrafish resolves DNA damage and preserves Purkinje cells and granule cells, revealing PAICS as a crucial mediator of cerebellar degeneration and a promising therapeutic avenue for C9orf72-associated ALS and FTD.<\/jats:p>","DOI":"10.1093\/brain\/awag092","type":"journal-article","created":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T12:35:04Z","timestamp":1773146104000},"page":"3475-3494","source":"Crossref","is-referenced-by-count":2,"title":["PAICS mediates DNA damage and cerebellar neuronal loss in C9orf72 amyotrophic lateral sclerosis"],"prefix":"10.1093","volume":"149","author":[{"given":"Jaskaran","family":"Singh","sequence":"first","affiliation":[{"name":"Institut National de la Recherche Scientifique (INRS), Centre Armand Frappier Sant\u00e9 Biotechnologie , Laval, QC H7V 1B7 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L\u00e9a","family":"Lescouz\u00e8res","sequence":"additional","affiliation":[{"name":"Institut National de la Recherche Scientifique (INRS), Centre Armand Frappier Sant\u00e9 Biotechnologie , Laval, QC H7V 1B7 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Zaouter","sequence":"additional","affiliation":[{"name":"Institut National de la Recherche Scientifique (INRS), Centre Armand Frappier Sant\u00e9 Biotechnologie , Laval, QC H7V 1B7 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathilde","family":"Chaineau","sequence":"additional","affiliation":[{"name":"Early Drug Discovery Unit (EDDU), The Neuro-Montreal Neurological Institute and Hospital, McGill University , Montreal, QC H3A 1A1 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ghazal","family":"Haghi","sequence":"additional","affiliation":[{"name":"Early Drug Discovery Unit (EDDU), The Neuro-Montreal Neurological Institute and Hospital, McGill University , Montreal, QC H3A 1A1 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas M","family":"Durcan","sequence":"additional","affiliation":[{"name":"Early Drug Discovery Unit (EDDU), The Neuro-Montreal Neurological Institute and Hospital, McGill University , Montreal, QC H3A 1A1 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunmoogum A","family":"Patten","sequence":"additional","affiliation":[{"name":"Institut National de la Recherche Scientifique (INRS), Centre Armand Frappier Sant\u00e9 Biotechnologie , Laval, QC H7V 1B7 ,","place":["Canada"]},{"name":"D\u00e9partement de Neurosciences, Universit\u00e9 de Montr\u00e9al , Montr\u00e9al, QC H3C 3J7 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