Dimerization of visinin-like protein 1 is regulated by oxidative stress and calcium and is a pathological hallmark of amyotrophic lateral sclerosis

Abstract

Redox control of proteins that form disulfide bonds upon oxidative challenge is an emerging topic in the physiological and pathophysiological regulation of protein function. We have investigated the role of the neuronal calcium sensor protein visinin-like protein 1 (VILIP-1) as a novel redox sensor in a cellular system. We have found oxidative stress to trigger dimerization of VILIP-1 within a cellular environment and identified thioredoxin reductase as responsible for facilitating the remonomerization of the dimeric protein. Dimerization is modulated by calcium and not dependent on the myristoylation of VILIP-1. Furthermore, we show by site-directed mutagenesis that dimerization is exclusively mediated by Cys187. As a functional consequence, VILIP-1 dimerization modulates the sensitivity of cells to an oxidative challenge. We have investigated whether dimerization of VILIP-1 occurs in two different animal models of amyotrophic lateral sclerosis (ALS) and detected soluble VILIP-1 dimers to be significantly enriched in the spinal cord from phenotypic disease onset onwards. Moreover, VILIP-1 is part of the ALS-specific protein aggregates. We show for the first time that the C-terminus of VILIP-1, containing Cys187, might represent a novel redox-sensitive motif and that VILIP-1 dimerization and aggregation are hallmarks of ALS. This suggests that VILIP-1 dimers play a functional role in integrating the cytosolic calcium concentration and the oxidative status of the cell. Furthermore, a loss of VILIP-1 function owing to protein aggregation in ALS could be relevant in the pathophysiology of the disease.

Longstanding psychological stress in relation to biomarkers of neuronal dysfunction in cerebrospinal fluid: a 25-year follow-up study in women

“…To gain new insights into the molecular pathology of stress, several pathophysiological pathways can be explored. VILIP-1 is a neuronal calcium sensor protein that is abundantly expressed in the brain, and plays a functional role in integrating the cytosolic calcium concentration and the oxidative status of the cell (Liebl et al, 2014). The protein has been demonstrated as a marker of neuronal injury and can be excessively released because of neuronal degradation (Lee et al, 2008).…”

Cross-talk between redox signalling and protein aggregation

“…As a result of aggregation, functional levels of VSNL1 are decreased, possibly providing a second mechanism to keep GC inactive besides calcium levels. Furthermore, VSNL1 aggregates are found in amyotrophic lateral sclerosis (ALS)-associated deposits, linking them to neuronal impairment [75][76][77][78][79].…”

Receptor-mediated endocytosis 8 (RME-8)/DNAJC13 is a novel positive modulator of autophagy and stabilizes cellular protein homeostasis

“…For transient expression, HEK293 cells were transfected by calcium phosphate precipitation as described earlier [48] and specified in the supplemental material. A set of two siR-NAs against DNAJC13 or nonsense siRNA (Suppl.…”