title: Protein clearing pathways in ALS.
abstract: In the present review a large amount of experimental and clinical studies on ALS are discussed in an effort to dissect common pathogenic mechanisms which may provide novel information and potential therapeutic strategies for motor neuron degeneration.Protein clearing systems play a critical role in motor neuron survival during excitotoxic stress, aging and neurodegenerative disorders. Among various mechanisms which clear proteins from the cell recent studies indicate autophagy as the most prominent pathway to promote survival of motor neurons.Autophagy regulates the clearance of damaged mitochondria, endoplasmic reticulum and misfolded proteins in eukaryotic cells. Upon recruitment of the autophagy pathway, an autophagosome is produced and directed towards lysosomal degradation.Here we provide evidence that in both genetic and sporadic amyotrophic lateral sclerosis (ALS, the most common motor neuron disorder) a defect in the autophagy machinery is common. In fact, swollen, disrupted mitochondria and intracellular protein aggregates accumulate within affected motor neurons. These structures localize within double membrane vacuoles, autophagosomes, which typically cluster in perinuclear position. In keeping with this, when using autophagy inhibitors or suppressing autophagy promoting genes, motor symptoms and motor neuron death are accelerated. Conversely stimulation of autophagy alleviates motor neuron degeneration.Therefore, autophagy represents an important target when developing novel treatments in ALS.
authors.affiliation: Department of Human Morphology and Applied Biology University of Pisa, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Ferrucci
authors.forename: Fedrica
authors.initials: F
authors.lastname: Fulceri
authors.forename: Luca
authors.initials: L
authors.lastname: Toti
authors.forename: Paola
authors.initials: P
authors.lastname: Soldani
authors.forename: Gabriele
authors.initials: G
authors.lastname: Siciliano
authors.forename: Antonio
authors.initials: A
authors.lastname: Paparelli
authors.forename: Francesco
authors.initials: F
authors.lastname: Fornai
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology / Q000627:therapeutic use; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D018021:Lithium Chloride / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000473:pathology / Q000502:physiology; D011506:Proteins / Q000378:metabolism*; D057165:Proteostasis Deficiencies / Q000378:metabolism / Q000503:physiopathology; D013482:Superoxide Dismutase / Q000235:genetics
chemical_list: D000276:Adjuvants, Immunologic; D011506:Proteins; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D018021:Lithium Chloride