title: Old versus New Mechanisms in the Pathogenesis of ALS.
abstract: Amyotrophic Lateral Sclerosis (ALS) is recognized as a very complex disease. As we have learned in the past 20 years from studies in patients and in models based on the expression of mutant SOD1, ALS is not a purely motor neuron disease as previously thought. While undoubtedly motor neurons are lost in patients, a number of alterations in those cell-types that interact functionally with motor neurons (astrocytes, microglia, muscle fibers, oligodendrocytes) take place even long before onset of symptoms. At the same time, disturbance of several, only partly inter-related physiological functions play some role in the onset and progression of the disease. Traditionally, mitochondrial damage and oxidative stress, excitotoxicity, neuroinflammation, altered axonal transport, ER stress, protein aggregation and defective removal of toxic proteins have been considered as key factors in the pathogenesis of ALS, with the relatively recent addition of disturbances in RNA metabolism. This complexity makes the search for an effective treatment extremely difficult and prompts further studies to reveal other possible, previously unappreciated aspects of the pathogenesis of ALS. In this review, we focus on previous knowledge on ALS mechanisms as well as new facets emerging from studies on genetic ALS patients and models that may both provide precious information for a novel therapeutic approach.
authors.affiliation: Institute of Translational Pharmacology, National Research Council (CNR), Rome, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Rossi
authors.affiliation: Institute of Translational Pharmacology, National Research Council (CNR), Rome, Italy.|Lab of Neurochemistry, Fondazione Santa Lucia IRCCS, Rome, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Cozzolino
authors.affiliation: Lab of Neurochemistry, Fondazione Santa Lucia IRCCS, Rome, Italy.|Department of Biology, University of Rome Tor Vergata.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Carrì
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000503:physiopathology* / Q000628:therapy; D000818:Animals; D006801:Humans
keywords: ALS; RNA metabolism; amyotrophic lateral sclerosis; motor neuron; protein aggregation