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Christianson syndrome involves endosome dysfunction leading to early cerebellar degeneration, as well as later-onset cortical and subcortical neurodegeneration, potentially including tau deposition as reported in post-mortem studies. In addition, there is reported evidence of modulation of amyloid-\u03b2 levels in experimental models wherein NHE6 expression was targeted. We have recently shown that loss of NHE6 causes defects in endosome maturation and trafficking underlying lysosome deficiency in primary mouse neurons in vitro. For in vivo studies, rat models may have an advantage over mouse models for the study of neurodegeneration, as rat brain can demonstrate robust deposition of endogenously-expressed amyloid-\u03b2 and tau in certain pathological states. Mouse models generally do not show the accumulation of insoluble, endogenously-expressed (non-transgenic) tau or amyloid-\u03b2. Therefore, to study neurodegeneration in Christianson syndrome and the possibility of amyloid-\u03b2 and tau pathology, we generated an NHE6-null rat model of Christianson syndrome using CRISPR-Cas9 genome-editing. Here, we present the sequence of pathogenic events in neurodegenerating NHE6-null male rat brains across the lifespan. NHE6-null rats demonstrated an early and rapid loss of Purkinje cells in the cerebellum, as well as a more protracted neurodegenerative course in the cerebrum. In both the cerebellum and cerebrum, lysosome deficiency is an early pathogenic event, preceding autophagic dysfunction. Microglial and astrocyte activation also occur early. In the hippocampus and cortex, lysosome defects precede loss of pyramidal cells. Importantly, we subsequently observed biochemical and in situ evidence of both amyloid-\u03b2 and tau aggregation in the aged NHE6-null hippocampus and cortex (but not in the cerebellum). Tau deposition is widely distributed, including cortical and subcortical distributions. Interestingly, we observed tau deposition in both neurons and glia, as has been reported in Christianson syndrome post-mortem studies previously. In summary, this experimental model is among very few examples of a genetically modified animal that exhibits neurodegeneration with deposition of endogenously-expressed amyloid-\u03b2 and tau. This NHE6-null rat will serve as a new robust model for Christianson syndrome. Furthermore, these studies provide evidence for linkages between endolysosome dysfunction and neurodegeneration involving protein aggregations, including amyloid-\u03b2 and tau. Therefore these studies may provide insight into mechanisms of more common neurodegenerative disorders, including Alzheimer\u2019s disease and related dementias.<\/jats:p>","DOI":"10.1093\/brain\/awab467","type":"journal-article","created":{"date-parts":[[2021,12,16]],"date-time":"2021-12-16T20:12:31Z","timestamp":1639685551000},"page":"3187-3202","source":"Crossref","is-referenced-by-count":32,"title":["Early lysosome defects precede neurodegeneration with amyloid-\u03b2 and tau aggregation in NHE6-null rat brain"],"prefix":"10.1093","volume":"145","author":[{"given":"YouJin","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Molecular Biology, Cell Biology and Biochemistry, Brown University , Providence, RI 02912 , USA"},{"name":"Center for Translational Neuroscience, Carney Institute for Brain Science and Brown Institute for Translational Science (BITS), Brown University , Providence, RI 02912 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morgan R","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Cell Biology and Biochemistry, Brown University , Providence, RI 02912 , USA"},{"name":"Center for Translational Neuroscience, Carney Institute for Brain Science and Brown Institute for Translational Science (BITS), Brown University , Providence, RI 02912 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marty A","family":"Fernandez","sequence":"additional","affiliation":[{"name":"Ann Romney Center for Neurologic Diseases, Brigham and Women\u2019s Hospital and Harvard Medical School , Boston, MA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth L","family":"Berg","sequence":"additional","affiliation":[{"name":"MIND Institute and Department of Psychiatry and Behavioural Sciences, University of California Davis School of Medicine , Sacramento, CA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana M","family":"Prada","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Cell Biology and Biochemistry, Brown University , Providence, RI 02912 , USA"},{"name":"Center for Translational Neuroscience, Carney Institute for Brain Science and Brown Institute for Translational Science (BITS), Brown University , Providence, RI 02912 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Ouyang","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Cell Biology and Biochemistry, Brown University , Providence, RI 02912 , USA"},{"name":"Center for Translational Neuroscience, Carney Institute for Brain Science and Brown Institute for Translational Science (BITS), Brown University , Providence, RI 02912 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Cell Biology and Biochemistry, Brown University , Providence, RI 02912 , USA"},{"name":"Center for Translational Neuroscience, Carney Institute for Brain Science and Brown Institute for Translational Science (BITS), Brown University , Providence, RI 02912 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill L","family":"Silverman","sequence":"additional","affiliation":[{"name":"MIND Institute and Department of Psychiatry and Behavioural Sciences, University of California Davis School of Medicine , Sacramento, CA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracy L","family":"Young-Pearse","sequence":"additional","affiliation":[{"name":"Ann Romney Center for Neurologic Diseases, Brigham and Women\u2019s Hospital and Harvard Medical School , Boston, MA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3430-3520","authenticated-orcid":false,"given":"Eric M","family":"Morrow","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Cell Biology and Biochemistry, Brown University , Providence, RI 02912 , USA"},{"name":"Center for Translational Neuroscience, Carney Institute for Brain Science and Brown Institute for Translational Science (BITS), Brown University , Providence, RI 02912 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,12,20]]},"reference":[{"key":"2023042819392001700_awab467-B1","doi-asserted-by":"crossref","first-page":"119","DOI":"10.3389\/fncel.2015.00119","article-title":"Adapting for endocytosis: roles for endocytic sorting adaptors in directing neural development","volume":"9","author":"Yap","year":"2015","journal-title":"Front Cell 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