CALSER

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, characterized by the selective degeneration of motoneurons (MNs), leading to muscle atrophy, paralysis and death within 3-5 years of diagnosis. There is no cure for ALS. Alteration in the buffering capacity of the proteostasis network and disturbances in the function of the endoplasmic reticulum (ER) is recognized as one of the triggering steps in the pathophysiology of ALS. Cerebral dopamine neurotrophic factor (CDNF) is a novel ER stress regulating protein that protects and restores dopaminergic neurons in rodent models of Parkinson’s disease (PD). CDNF with its unique structure and mode of action is mainly ER localized, but can be secreted and function as a growth factor. CDNF reduces ER stress and diminishes the level of pro-inflammatory cytokines. Compared to other neurotrophic factors (NTFs), novel variant of CDNF (C-CDNF) can pass through the (blood-brain-barrier (BBB), spreading with high efficiency across the brain tissue and remarkably, acts only on injured or stressed cells. Similar, to other NTFs, CDNF and C-CDNF also block apoptosis. CDNF expression is not restricted to the brain but also found in both MNs and muscles. CDNF knockout mice show prominent motor deficits and in this context, it is essential to test whether CDNF and CCDNF, promote the survival of MNs and reduce ER stress in preclinical rodent models of ALS expressing either mutant SOD1 or TDP-43. Importantly, we would like to examine how CDNF and C-CDNF regulate ER stress responses and identify the precise unfolded protein response (UPR) pathways affected, which eventually might alter survival and functionality of MNs derived from ALS animal models and MNs generated from ALS patient-derived iPS cells. The objective of this proposal is to perform preclinical experiments in order to extend our promising in vivo findings with novel NTFs CDNF and C-CDNF from SOD1 mice model of ALS to other model of ALS and eventually translate the results for the benefit of patients living with ALS. Our preliminary data reveal that CDNF and its novel fragment that are currently the best therapeutic candidates for ALS.