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Both dysfunction in autophagy and neuroinflammation have been linked to TDP\u201043\u00a0mislocalisation. Here, we investigate TDP\u201043 proteinopathy in Niemann\u2010Pick type C disease (NPC), an autosomal recessive lysosomal storage disease (LSD) distinguished by the accumulation of unesterified cholesterol within late endosomes and lysosomes. NPC is characterised by neurodegeneration, neuroinflammation and multifocal disruption of the autophagy pathway.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We utilised immunohistochemistry, confocal microscopy, electron microscopy and biochemical and gene expression studies to characterise TDP\u201043 pathology and autophagic substrate accumulation in\n                      <jats:italic>Npc1<\/jats:italic>\n                      \u2010deficient mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In the NPC brain, cytoplasmic TDP\u201043\u00a0mislocalisation was independent of autophagic substrate accumulation. These pathologies occurred in distinct neuronal subtypes, as brainstem cholinergic neurons were more susceptible to TDP\u201043\u00a0mislocalisation, whereas glutamatergic neurons exhibited hallmarks of autophagic dysfunction. Furthermore, TDP\u201043\u00a0mislocalisation did not co\u2010localise with markers of stress granules or progress to ubiquitinated aggregates over months in vivo, indicating a stable, early stage in the aggregation process. Neither microgliosis nor neuroinflammation were sufficient to drive TDP\u201043 proteinopathy in the NPC brain. Notably, cytoplasmic TDP\u201043 co\u2010localised with the nuclear import factor importin \u03b1, and TDP\u201043\u00a0mislocalised neurons demonstrated nuclear membrane abnormalities and disruption of nucleocytoplasmic transport.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings highlight the relationship between LSDs and TDP\u201043 proteinopathy, define its functional importance in NPC by triggering nuclear dysfunction, and expand the spectrum of TDP\u201043 pathology in the diseased brain.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/nan.12738","type":"journal-article","created":{"date-parts":[[2021,5,28]],"date-time":"2021-05-28T10:34:18Z","timestamp":1622198058000},"page":"1019-1032","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["TDP\u201043 proteinopathy occurs independently of autophagic substrate accumulation and underlies nuclear defects in Niemann\u2010Pick C disease"],"prefix":"10.1111","volume":"47","author":[{"given":"Elaine A.","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Pathology University of Michigan Medical School  Ann Arbor MI USA"},{"name":"Cellular and Molecular Biology Graduate Program University of Michigan Medical School  Ann Arbor MI USA"},{"name":"Medical Scientist Training Program University of Michigan Medical School  Ann Arbor MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika","family":"Mori","sequence":"additional","affiliation":[{"name":"Yamaguchi University School of Medicine  Ube Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fuko","family":"Hamasaki","sequence":"additional","affiliation":[{"name":"Yamaguchi University School of Medicine  Ube Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew 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