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A key pathological feature of the disease is the presence of heavily ubiquitinated protein inclusions. Both the unfolded protein response and the ubiquitin\u2013proteasome system appear significantly impaired in patients and animal models of ALS. We have studied cellular and molecular mechanisms involved in ALS using a vesicle-associated membrane protein-associated protein B (VAPB\/ALS8) Drosophila model [Moustaqim-Barrette, A., Lin, Y.Q., Pradhan, S., Neely, G.G., Bellen, H.J. and Tsuda, H. (2014) The ALS 8 protein, VAP, is required for ER protein quality control. Hum. Mol. Genet., 23, 1975\u20131989], which mimics many systemic aspects of the human disease. Here, we show that VAPB, located on the cytoplasmic face of the endoplasmic reticulum membrane, interacts with Caspar, an orthologue of human fas associated factor 1 (FAF1). Caspar, in turn, interacts with transitional endoplasmic reticulum ATPase (TER94), a fly orthologue of ALS14 (VCP\/p97, valosin-containing protein). Caspar overexpression in the glia extends lifespan and also slows the progression of motor dysfunction in the ALS8 disease model, a phenomenon that we ascribe to its ability to restrain age-dependent inflammation, which is modulated by Relish\/NF\u03baB signalling. Caspar binds to VAPB via an FFAT motif, and we find that Caspar\u2019s ability to negatively regulate NF\u03baB signalling is not dependent on the VAPB:Caspar interaction. We hypothesize that Caspar is a key molecule in the pathogenesis of ALS. The VAPB:Caspar:TER94 complex appears to be a candidate for regulating both protein homeostasis and NF\u03baB signalling, with our study highlighting a role for Caspar in glial inflammation. We project human FAF1 as an important protein target to alleviate the progression of motor neuron disease.<\/jats:p>","DOI":"10.1093\/hmg\/ddac076","type":"journal-article","created":{"date-parts":[[2022,4,4]],"date-time":"2022-04-04T13:31:18Z","timestamp":1649079078000},"page":"2857-2875","source":"Crossref","is-referenced-by-count":19,"title":["Caspar, an adapter for VAPB and TER94, modulates the progression of ALS8 by regulating IMD\/NF\u03baB-mediated glial inflammation in a<i>Drosophila<\/i>model of human disease"],"prefix":"10.1093","volume":"31","author":[{"given":"Shweta","family":"Tendulkar","sequence":"first","affiliation":[{"name":"Department of Biology, Indian Institute of Science Education and Research (IISER) , Pune 411008 , India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sushmitha","family":"Hegde","sequence":"additional","affiliation":[{"name":"Department of Biology, Indian Institute of Science Education and Research (IISER) , Pune 411008 , India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lovleen","family":"Garg","sequence":"additional","affiliation":[{"name":"Department of Biology, Indian Institute of Science Education and Research (IISER) , Pune 411008 , India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aparna","family":"Thulasidharan","sequence":"additional","affiliation":[{"name":"Department of Biology, Indian Institute of Science Education and Research (IISER) , Pune 411008 , India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bhagyashree","family":"Kaduskar","sequence":"additional","affiliation":[{"name":"Department of Biology, Indian Institute of Science Education and Research (IISER) , Pune 411008 , India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anuradha","family":"Ratnaparkhi","sequence":"additional","affiliation":[{"name":"Developmental Biology Group, MACS-Agharkar Research Institute , Pune 411004 , India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7615-3140","authenticated-orcid":false,"given":"Girish S","family":"Ratnaparkhi","sequence":"additional","affiliation":[{"name":"Department of Biology, Indian Institute of Science Education and Research (IISER) , Pune 411008 , India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,4,4]]},"reference":[{"key":"2022090105185677000_ref1","doi-asserted-by":"crossref","first-page":"2031","DOI":"10.1016\/S0140-6736(07)60944-1","article-title":"Amyotrophic lateral sclerosis","volume":"369","author":"Mitchell","year":"2007","journal-title":"Lancet"},{"key":"2022090105185677000_ref2","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1038\/nrn1971","article-title":"Molecular biology of amyotrophic lateral sclerosis: insights from genetics","volume":"7","author":"Pasinelli","year":"2006","journal-title":"Nat. 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Neurosci."},{"key":"2022090105185677000_ref4","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1126\/science.8351519","article-title":"Amyotrophic lateral sclerosis and structural defects in Cu,Zn superoxide dismutase","volume":"261","author":"Deng","year":"1993","journal-title":"Science"},{"key":"2022090105185677000_ref5","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1038\/362059a0","article-title":"Mutations in cu\/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis","volume":"362","author":"Rosen","year":"1993","journal-title":"Nature"},{"key":"2022090105185677000_ref6","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1002\/humu.22157","article-title":"ALSoD: a user-friendly online bioinformatics tool for amyotrophic lateral sclerosis genetics","volume":"33","author":"Abel","year":"2012","journal-title":"Hum. 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