RRC ID 70373
Author Tendulkar S, Hegde S, Garg L, Thulasidharan A, Kaduskar B, Ratnaparkhi A, Ratnaparkhi GS.
Title Caspar, an adapter for VAPB and TER94, modulates the progression of ALS8 by regulating IMD/NFκB-mediated glial inflammation in a Drosophila model of human disease.
Journal Hum Mol Genet
Abstract Amyotrophic Lateral Sclerosis (ALS) is a fatal, late-onset, progressive motor neurodegenerative disorder. A key pathological feature of the disease is the presence of heavily ubiquitinated protein inclusions. Both the Unfolded Protein Response (UPR) and the Ubiquitin Proteasome System (UPS) 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 et al., 2014), which mimics many systemic aspects of the human disease. Here, we show that VAPB, located on the cytoplasmic face of the ER membrane, interacts with Caspar, an ortholog of human fas associated factor 1 (FAF1). Caspar, in turn, interacts with transitional endoplasmic reticulum ATPase (TER94), a fly ortholog 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-dependant inflammation, which is modulated by Relish/NFκB signalling. Caspar binds to VAPB via an FFAT motif, and we find that Caspar's ability to negatively regulate NFκB signalling is not dependant 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 NFκB 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.
Volume 31(17)
Pages 2857-2875
Published 2022-8-25
DOI 10.1093/hmg/ddac076
PII 6563110
PMID 35377453
PMC PMC9433731
MeSH Adaptor Proteins, Signal Transducing / metabolism Amyotrophic Lateral Sclerosis* / metabolism Animals Apoptosis Regulatory Proteins / metabolism Drosophila / genetics Drosophila / metabolism Humans Inflammation / genetics Inflammation / pathology Mutation Nerve Degeneration / pathology Neuroglia / metabolism Ubiquitin / metabolism Vesicular Transport Proteins / metabolism
IF 5.101