{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:19:28Z","timestamp":1792790368886,"version":"4.5.0"},"posted":{"date-parts":[[2026,9,28]]},"group-title":"Neuroscience","reference-count":111,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"National Institute on Aging","award":["R01AG078788"],"award-info":[{"award-number":["R01AG078788"]}],"id":[{"id":"https:\/\/ror.org\/049v75w11","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Institute on Aging","award":["R01AG076493"],"award-info":[{"award-number":["R01AG076493"]}],"id":[{"id":"https:\/\/ror.org\/049v75w11","id-type":"ROR","asserted-by":"crossref"}]},{"award":["GM150832"],"award-info":[{"award-number":["GM150832"]}],"id":[{"id":"https:\/\/ror.org\/04q48ey07","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Cancer Prevention and Research Institute of Texas","award":["RR220021"],"award-info":[{"award-number":["RR220021"]}],"id":[{"id":"https:\/\/ror.org\/0003xa228","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  A key pathophysiological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is loss of nuclear localization and abnormal cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP-43). Upstream factors that trigger the onset and progression of such neurodegenerative diseases are largely unknown. Aging and environmental factors contribute as potential risk factors. But epidemiological evidence suggests psychological stressors such as social isolation and loneliness are also associated with increased risks of neurodegenerative disease [1\u20138]. We examined the impacts of social isolation on TDP-43 related neurodegeneration. To investigate the potential for causative impact on neurodegeneration, we compared the effects of social isolation versus social enrichment in\n                  <jats:italic>Drosophila<\/jats:italic>\n                  . We utilized an established social isolation paradigm in which flies were either housed alone or in groups as young adults. We found that early-life social isolation acts as a primer to exacerbate the rate of neurodegeneration in response to subsequent induction of pathological levels of TDP-43. Social isolation stress drives more rapid activation of mdg4, an endogenous retrovirus that functionally mediates TDP-43 effects and more aggressive propagation of TDP-43 protein pathology from surface glial cells to nearby neurons. Shortened life span also ensues. We demonstrate that providing isolated flies with visual, olfactory and tactile social cues from conspecifics living behind a divider was insufficient to alleviate these effects of social isolation on neurodegeneration. Our findings have implications for the association between psychological stressors such as loneliness and risk of neurodegenerative diseases in humans and provide a platform to investigate mechanistic underpinnings in animal models.\n                <\/jats:p>","DOI":"10.64898\/2026.09.23.753732","type":"posted-content","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T04:10:15Z","timestamp":1790655015000},"source":"Crossref","is-referenced-by-count":1,"title":["Early life social isolation primes flies for more rapid TDP-43 dependent neurodegeneration later in life"],"prefix":"10.64898","author":[{"given":"S.","family":"MurthyGowda","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Stony Brook School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K.","family":"Huyghue","sequence":"additional","affiliation":[{"name":"Health Sciences Stony Brook University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B.","family":"Castillo","sequence":"additional","affiliation":[{"name":"Dept of Biology, Texas A&M University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F.","family":"Gugala","sequence":"additional","affiliation":[{"name":"Dept of Biology, Texas A&M University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5682-5173","authenticated-orcid":false,"given":"W.","family":"Li","sequence":"additional","affiliation":[{"name":"Dept of Biology, Texas A&M University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9285-7444","authenticated-orcid":false,"given":"J.","family":"Dubnau","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Stony Brook School of Medicine"},{"name":"Department of Neurobiology and Behaviour, Stony Brook University"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026100607201335000_2026.09.23.753732v2.1","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2017-019399"},{"key":"2026100607201335000_2026.09.23.753732v2.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2020.01.026"},{"issue":"1","key":"2026100607201335000_2026.09.23.753732v2.3","doi-asserted-by":"crossref","first-page":"4314","DOI":"10.1038\/s41467-022-31873-5","article-title":"Shared mechanisms across the major psychiatric and neurodegenerative diseases","volume":"13","year":"2022","journal-title":"Nature communications"},{"key":"2026100607201335000_2026.09.23.753732v2.4","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.98.18_supplement.1337"},{"issue":"2","key":"2026100607201335000_2026.09.23.753732v2.5","first-page":"e164","article-title":"Associations of social isolation and loneliness with later dementia","volume":"99","year":"2022","journal-title":"Neurology"},{"issue":"11","key":"2026100607201335000_2026.09.23.753732v2.6","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.1001\/jamaneurol.2023.3382","article-title":"Loneliness and risk of Parkinson disease","volume":"80","year":"2023","journal-title":"JAMA neurology"},{"issue":"6","key":"2026100607201335000_2026.09.23.753732v2.7","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1017\/S1041610222001028","article-title":"Loneliness and risk of all-cause, Alzheimer\u2019s, vascular, and frontotemporal dementia: a prospective study of 492,322 individuals over 15 years","volume":"35","year":"2023","journal-title":"International Psychogeriatrics"},{"key":"2026100607201335000_2026.09.23.753732v2.8","doi-asserted-by":"crossref","unstructured":"Zimmerman SC , Chen R , Thoma M , Pacca L , Hebert J , Riley A , et al. 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