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.

Amyotrophic Lateral Sclerosis (ALS) is a fatal, late-onset, progressive motor neurodegenerative disorder. We have been studying cellular and molecular mechanisms involved in ALS using a vesicle-associated membrane protein-associated protein B (VAPB/ALS8) Drosophila model, which mimics many systemic aspects of the human disease. Here, we show that the ER-resident VAPB 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), via its UBX domain and poly-ubiquitinated proteins with its UBA domain. Caspar overexpression in the glia extends lifespan and also slows the progression of motor dysfunction in the ALS8 model, a phenomenon that we ascribe to its ability to restrain age-dependant inflammation, modulated by Relish/NFBκ signaling. We hypothesize that Caspar is a key molecule in the pathogenesis of ALS. Caspar connects the plasma membrane (PM) localized immune signalosome to the ER-based VAPB degradative machinery, presumably at PM:ER contact sites. The Caspar:TER94:VAPB complex appears to be a strong candidate for regulating both protein homeostasis and NFκ signaling. These, in turn, regulate glial inflammation and determine the progression of the disease. Our study projects human FAF1 as an important protein target to alleviate the progression of motor neuron disease.