Molecular and Physiological Determinants of Amyotrophic Lateral Sclerosis: What the DJ-1 Protein Teaches Us
-
Published:2023-04-21
Issue:8
Volume:24
Page:7674
-
ISSN:1422-0067
-
Container-title:International Journal of Molecular Sciences
-
language:en
-
Short-container-title:IJMS
Author:
Sandrelli Federica1ORCID, Bisaglia Marco12ORCID
Affiliation:
1. Department of Biology, University of Padova, 35131 Padova, Italy 2. Study Center for Neurodegeneration (CESNE), 35100 Padova, Italy
Abstract
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.
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis
Reference108 articles.
1. Mejzini, R., Flynn, L.L., Pitout, I.L., Fletcher, S., Wilton, S.D., and Akkari, P.A. (2019). ALS Genetics, Mechanisms, and Therapeutics: Where Are We Now?. Front. Neurosci., 13. 2. Mutations in Cu/Zn Superoxide Dismutase Gene Are Associated with Familial Amyotrophic Lateral Sclerosis;Rosen;Nature,1993 3. Wright, G.S.A., Antonyuk, S.V., and Hasnain, S.S. (2019). The Biophysics of Superoxide Dismutase-1 and Amyotrophic Lateral Sclerosis. Q. Rev. Biophys., 52. 4. Superoxide Dismutase 1 in Health and Disease: How a Frontline Antioxidant Becomes Neurotoxic;Trist;Angew. Chem. Int. Ed. Engl.,2021 5. Hilton, J.B., Mercer, S.W., Lim, N.K.H., Faux, N.G., Buncic, G., Beckman, J.S., Roberts, B.R., Donnelly, P.S., White, A.R., and Crouch, P.J. (2017). CuII(Atsm) Improves the Neurological Phenotype and Survival of SOD1G93A Mice and Selectively Increases Enzymatically Active SOD1 in the Spinal Cord. Sci. Rep., 7.
|
|