Molecular and Physiological Determinants of Amyotrophic Lateral Sclerosis: What the DJ-1 Protein Teaches Us

Amyotrophic lateral sclerosis (ALS) is an adult-onset disease which causes the progressive degeneration of cortical and spinal motoneurons, leading to death a few years after the first symptom onset. ALS is mainly a sporadic disorder, and its causative mechanisms are mostly unclear. About 5-10% of cases have a genetic inheritance, and the study of ALS-associated genes has been fundamental in defining the pathological pathways likely also involved in the sporadic forms of the disease. Mutations affecting the DJ-1 gene appear to explain a subset of familial ALS forms. DJ-1 is involved in multiple molecular mechanisms, acting primarily as a protective agent against oxidative stress. Here, we focus on the involvement of DJ-1 in interconnected cellular functions related to mitochondrial homeostasis, reactive oxygen species (ROS) levels, energy metabolism, and hypoxia response, in both physiological and pathological conditions. We discuss the possibility that impairments in one of these pathways may affect the others, contributing to a pathological background in which additional environmental or genetic factors may act in favor of the onset and/or progression of ALS. These pathways may represent potential therapeutic targets to reduce the likelihood of developing ALS and/or slow disease progression.

Automated summary

Amyotrophic lateral sclerosis (ALS) is a progressive disease that primarily affects the motor neurons of the cortex and spinal cord, resulting in death a few years after symptom onset. While most cases of ALS are sporadic, about 5-10% have a genetic component. The study of ALS-associated genes, particularly mutations in the DJ-1 gene, has provided insights into the pathological mechanisms of both familial and sporadic ALS. DJ-1 is involved in various cellular functions related to oxidative stress, mitochondrial homeostasis, energy metabolism, and hypoxia response, which may contribute to the development and progression of ALS. Targeting these pathways could potentially offer therapeutic strategies for ALS prevention and treatment.