DJ-1 products glycolic acid and D-lactate restore deficient axonal trafficking and DNA damage response in FUS and SOD1-associated amyotrophic lateral sclerosis

Abstract

AbstractAmyotrophic Lateral Sclerosis (ALS) is the most common motor neuron disease leading to death within 2-5 years. Currently available drugs can only slightly prolong survival. Despite the progress that has been achieved in unravelling the molecular mechanisms of the disease so far, the underlying pathophysiology is not fully understood. We present novel insights into the pathophysiology ofSuperoxide Dismutase 1(SOD1)- and in particularFused In Sarcoma(FUS)-ALS by revealing a putatively central role of the Parkinson’s disease (PD) associated glyoxylase DJ-1 and its products glycolic acid (GA) and D-lactic acid (DL). Combined, but not single, treatment with GA and DL restored axonal trafficking deficits of mitochondria and lysosomes in FUS- and SOD1-ALS patient-derived motoneurons (MNs). This was accompanied by restoration of mitochondrial membrane potential as well as mitochondrial fragmentation (FUS-ALS) or elongation (SOD1-ALS). Furthermore, GA and DL restored cytoplasmic mislocalization of FUS and FUS recruitment to DNA damage sites. We further show that despite presenting an early axonal transport deficiency as well, TDP-43 patient-derived MNs did not share this mechanism. While this points towards the necessity of individualized (gene-) specific therapy stratification, it also suggests common therapeutic targets across different gene variants of ALS. Thus, we introduce a putative novel treatment for ALS based on a combination of the two substances GA and DL which might be not only an interesting novel drug candidate in subsets of ALS cases but also in other neurodegenerative diseases characterized by mitochondrial depolarization.