Prof. Smita Saxena, Institute of Cell Biology, University of Bern

Abstract

Amyotrophic Lateral Sclerosis (ALS) or Motoneuron disease (MND) is an autosomal dominantly inherited neurodegenerative disease (ND), affecting upper and lower motoneurons (MN). Point mutations within the superoxide dismutase 1 (SOD1) gene leading to toxic gain of function have been causally implicated in familial cases of ALS (FALS). Although large majority of cases of ALS are sporadic, both familial and sporadic forms share similar clinical and pathological features suggesting that both forms might share common mechanisms of dysfunction. Despite several decades of research based on mouse models over-expressing human SOD1 point mutations, the precise mechanism by which mutated SOD1 causes selectively MN degeneration is not yet understood.

We have previously shown that one subtype of MN is selectively vulnerable to disease and that these vulnerable MN are prone to ER stress from birth onwards. We have further provided causality by showing that chronic build up of ER stress eventually leads to unfolded protein response (UPR) within vulnerable MN which is followed by denervation of their target muscle fiber. Recently, we have identified an ER resident nucleotide exchange factor (NEF) that is expressed at high levels within disease resistant MN but not in vulnerable MN. Further experiments revealed that high levels of NEF expression within MN and other neurons directly correlates with providing resistance to ER stress. Moreover, in vitro studies, using conformation specific antibodies revealed that NEF overexpression prevented the accumulation and aggregation of misfolded SOD1 within the ER. Loss of function studies using nef -/- mice crossed with SOD1G93A, interestingly now led to ER stress within resistant MN and anticipation of disease, suggesting that NEF is a bona fide candidate for further investigation in diseases where ER stress has been causally linked to the pathology.

Since ER stress responses have been causally associated with a wide spectrum of degenerative diseases of the nervous system, muscles and metabolic disorders, the identification of NEF as a positive modifier of ER stress and disease process provides an exciting opportunity for therapeutic interventions. Based on our novel results this research grant aims to explore the possibility of targeting this cellular stress response within MN in disease. Herein we propose to use Adeno-associated viruses (AAV) to overexpress NEF within MN, in an attempt to inhibit ER stress and provide axonal protection and delay manifestation of pathology. Accumulating evidences from several other degenerative diseases point towards dysfunctional cellular homeostasis and progressive cellular stress eventually leading to degeneration. Therefore a novel approach of targeting a cellular stress response directly implicated with degeneration, can serve as a valuable therapeutic approach.