{"doi":"10.1111/bpa.12903","title":"Aged <i>Tmem106b</i> knockout mice display gait deficits in coincidence with Purkinje cell loss and only limited signs of non‐motor dysfunction","abstract":"<jats:title>Abstract</jats:title><jats:p>Genetic variants in <jats:italic>TMEM106B</jats:italic> are a major risk factor for several neurodegenerative diseases including frontotemporal degeneration, limbic‐predominant age‐related TDP‐43 encephalopathy, Parkinson's disease, late‐onset‐Alzheimer's disease and constitute a genetic determinant of differential aging. <jats:italic>TMEM106B</jats:italic> encodes an integral lysosomal membrane protein but its precise physiological function in the central nervous system remains enigmatic. Presently, we aimed to increase understanding of TMEM106B contribution to general brain function and aging. We analyzed an aged cohort of <jats:italic>Tmem106b</jats:italic> knockout‐, heterozygote and wild‐type mice in a behavioral test battery including assessments of motor function as well as, social, emotional and cognitive function. Aged <jats:italic>Tmem106b</jats:italic> knockout (KO) mice displayed diverse behavioral deficits including motor impairment, gait defects and reduced startle reactivity. In contrast, no prominent deficits were observed in social, emotional or cognitive behaviors. Histologically, we observed late‐onset loss of Purkinje cells followed by reactive gliosis in the cerebellum, which likely contributed to progressive decline in motor function and gait defects in particular. Reactive gliosis was not restricted to the cerebellum but observed in different areas of the brain including the brain stem and parts of the cerebral cortex. Surviving Purkinje cells showed vacuolated lysosomes in the axon initial segment, implicating TMEM106B‐dependent lysosomal trafficking defects as the underlying cause of axonal and more general neuronal dysfunction contributing to behavioral impairments. Our experiments help to elucidate how TMEM106B affects spatial neuronal homeostasis and exemplifies a critical role of TMEM106B in neuronal cells for survival.</jats:p>","journal":"Brain Pathology","year":2021,"id":613652,"datarank":0.4943755299006494,"base_score":3.295836866004329,"endowment":3.295836866004329,"self_citation_contribution":0.4943755299006494,"citation_network_contribution":0.0,"self_endowment_contribution":0.4943755299006494,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":26,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1581019,"name":"Rudi D’Hooge","orcid":"0000-0003-2243-2106","position":1,"is_corresponding":false},{"id":693647,"name":"Markus Daμμe","orcid":"0000-0002-9699-9351","position":2,"is_corresponding":false},{"id":511326,"name":"Stijn Stroobants","orcid":"0000-0002-7838-824X","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Aged <i>Tmem106b</i> knockout mice display gait deficits in coincidence with Purkinje cell loss and only limited signs of non‐motor dysfunction","abstract":"<jats:title>Abstract</jats:title><jats:p>Genetic variants in <jats:italic>TMEM106B</jats:italic> are a major risk factor for several neurodegenerative diseases including frontotemporal degeneration, limbic‐predominant age‐related TDP‐43 encephalopathy, Parkinson's disease, late‐onset‐Alzheimer's disease and constitute a genetic determinant of differential aging. <jats:italic>TMEM106B</jats:italic> encodes an integral lysosomal membrane protein but its precise physiological function in the central nervous system remains enigmatic. Presently, we aimed to increase understanding of TMEM106B contribution to general brain function and aging. We analyzed an aged cohort of <jats:italic>Tmem106b</jats:italic> knockout‐, heterozygote and wild‐type mice in a behavioral test battery including assessments of motor function as well as, social, emotional and cognitive function. Aged <jats:italic>Tmem106b</jats:italic> knockout (KO) mice displayed diverse behavioral deficits including motor impairment, gait defects and reduced startle reactivity. In contrast, no prominent deficits were observed in social, emotional or cognitive behaviors. Histologically, we observed late‐onset loss of Purkinje cells followed by reactive gliosis in the cerebellum, which likely contributed to progressive decline in motor function and gait defects in particular. Reactive gliosis was not restricted to the cerebellum but observed in different areas of the brain including the brain stem and parts of the cerebral cortex. Surviving Purkinje cells showed vacuolated lysosomes in the axon initial segment, implicating TMEM106B‐dependent lysosomal trafficking defects as the underlying cause of axonal and more general neuronal dysfunction contributing to behavioral impairments. Our experiments help to elucidate how TMEM106B affects spatial neuronal homeostasis and exemplifies a critical role of TMEM106B in neuronal cells for survival.</jats:p>","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"33016371","pmcid":"PMC8018119","openalex_id":"https://openalex.org/W33016371","authors":[],"funders":[{"funder_name":"Fundação para a Ciência e a Tecnologia, I.P.","grant_id":"Incentivo/SAU/LA0002/2013","title":"Incentive - LA 2 - 2013"},{"funder_name":"Christian-Albrechts-Universität zu Kiel","grant_id":"","title":null},{"funder_name":"Christian-Albrechts-University Kiel","grant_id":"","title":null},{"funder_name":"Christian-Albrechts-University Kiel","grant_id":"","title":null}],"total_grants":4,"fwci":0.0,"citation_percentile":0.00947473,"influential_citations":0,"citation_trend":[],"oa_status":"hybrid","license":"cc-by-nc","oa_locations":[{"url":"https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/bpa.12903","host_type":"publisher"},{"url":"https://onlinelibrary.wiley.com/doi/pdf/10.1111/bpa.12903","host_type":"publisher"},{"url":"https://onlinelibrary.wiley.com/doi/full-xml/10.1111/bpa.12903","host_type":"publisher"},{"url":"http://cmslive.curriculum.edu.au/leader/default.asp?id=11225&issueID=9793","host_type":""},{"url":"https://lirias.kuleuven.be/handle/123456789/666498","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/8018119","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC8018119","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC8018119?pdf=render","host_type":"Europe_PMC"},{"url":"https://doi.org/10.1111/bpa.12903","host_type":""},{"url":"https://pubmed.ncbi.nlm.nih.gov/33016371","host_type":""},{"url":"http://dx.doi.org/10.1111/bpa.12903","host_type":""},{"url":"https://dx.doi.org/10.1111/bpa.12903","host_type":""}],"fields_of_study":["Education Systems and Policy","03 medical and health sciences","0302 clinical medicine","Aging","Animals","Behavior, Animal","Female","Lameness, Animal","Membrane Proteins","Mice","Mice, Inbred C57BL","Mice, Knockout","Nerve Tissue Proteins","Neurodegenerative Diseases","Purkinje Cells"],"mesh_terms":["Purkinje Cells","Animals","Mice, Inbred C57BL","Mice, Knockout","Mice","Neurodegenerative Diseases","Lameness, Animal","Membrane Proteins","Nerve Tissue Proteins","Behavior, Animal","Aging","Female"],"keywords":["Political science","Scale (ratio)","National interest","Library science","Geography","Computer science","Law","Cartography","Behavior","Purkinje cells","Lysosomes","Cerebellar Degeneration","Ftd","Tmem106b","EXPRESSION","Aging","GENETICS","TDP-43","Lameness, Animal","Clinical Neurology","Nerve Tissue Proteins","VARIANTS","DISEASE","Mice","MOUSE MODELS","Pathology","Animals","Research Articles","Mice, Knockout","FRONTOTEMPORAL LOBAR DEGENERATION","Science & Technology","Neurology & Neurosurgery","Behavior, Animal","DEMENTIA","Neurosciences","3202 Clinical sciences","Membrane Proteins","1103 Clinical Sciences","Neurodegenerative Diseases","Mice, Inbred C57BL","RISK-FACTOR TMEM106B","3209 Neurosciences","Female","Neurosciences & Neurology","1109 Neurosciences","Life Sciences & Biomedicine"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. 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