Caspar, an adapter for VAP and TER94 delays progression of disease by regulating glial inflammation in aDrosophilamodel of ALS8

Abstract

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.

The Link between VAPB Loss of Function and Amyotrophic Lateral Sclerosis

“…Indeed, as pointed out in the introductory section of this review, VAP deficit has been implicated in SOD1linked and sporadic ALS, and malfolded VAPB in peripheral blood mononuclear cells has been suggested as a possible diagnostic biomarker for ALS [26]. Furthermore, VAP deficit in Drosophila glial cells has been proposed to cause neuroinflammation, suggesting a VAPB-linked non-cell autonomous mechanism underlying MN death [211]. These phenomena broaden the scope of future research aimed at generating knowledge on the VAPs as well as on the pathogenic mechanisms of VAPB loss-of-function, which will hopefully translate to the clinic.…”