{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T04:07:10Z","timestamp":1789704430307,"version":"4.0.1"},"reference-count":155,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T00:00:00Z","timestamp":1782691200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T00:00:00Z","timestamp":1782691200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100000406","name":"Motor Neurone Disease Association","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000406","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Neuropathology Appl Neurobio"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a fatal neurodegenerative disease primarily affecting motor neurons. Two key protein inclusions found in lower motor neurons serve as neuropathological hallmarks of the disease in human tissue: the TDP43\u2010positive inclusion and the cystatin C\u2010positive Bunina body. Despite their diagnostic specificity and presence in most sporadic and familial ALS cases, Bunina bodies remain poorly understood, and their true prevalence is likely underestimated. The co\u2010occurrence of the Bunina body and the TDP43 inclusion may provide valuable insights into the development of TDP43 pathology in ALS. Thorough characterisation of the Bunina body is needed to understand this interplay and the broader pathomechanisms of disease. This review examines our current knowledge of Bunina bodies and the biochemical properties of cystatin C that may promote its aggregation. Sequestration and aggregation of cystatin C into Bunina bodies may diminish its neuroprotective functions, including cysteine protease inhibition, autophagy induction and anti\u2010amyloidogenic activity, thereby contributing to ALS pathogenesis. This review also evaluates findings from human post\u2010mortem tissue and ALS disease models, discussing the value and limitations of these models in the context of Bunina bodies and TDP43 pathology. Finally, we discuss cystatin C's use as a biomarker and its therapeutic potential. A deeper understanding of cystatin C biology, its relationship with TDP43 pathology and improved ALS models will be essential for determining whether targeting cystatin C could provide a viable avenue for future ALS therapies.<\/jats:p>","DOI":"10.1111\/nan.70083","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T02:55:56Z","timestamp":1782788156000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Unravelling the Significance of Cystatin C and Bunina Bodies in Amyotrophic Lateral Sclerosis Pathogenesis"],"prefix":"10.1111","volume":"52","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-3783-4307","authenticated-orcid":false,"given":"Sarah M.","family":"Granger","sequence":"first","affiliation":[{"name":"University of Sheffield  Sheffield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosemary A.","family":"Staniforth","sequence":"additional","affiliation":[{"name":"University of Sheffield  Sheffield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9753-8726","authenticated-orcid":false,"given":"Asbjorg Osk","family":"Snorradottir","sequence":"additional","affiliation":[{"name":"Department of Pathology Landspitali\u2014The National University Hospital of Iceland  Reykjavik Iceland"},{"name":"Arctic Therapeutics  Reykjavik Iceland"},{"name":"Faculty of Medicine University of Iceland  Reykjavik Iceland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johnathan","family":"Cooper\u2010Knock","sequence":"additional","affiliation":[{"name":"University of Sheffield  Sheffield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kurt J.","family":"De Vos","sequence":"additional","affiliation":[{"name":"University of Sheffield  Sheffield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4969-6526","authenticated-orcid":false,"given":"J. 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