title: The role of autophagy: what can be learned from the genetic forms of amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder caused by loss of motor neurons both in the brain and spinal cord, which dramatically reduces life expectancy. ALS occurs either in familial ALS or, more frequently, in sporadic ALS forms. Several mechanisms have been postulated to underlie motor neuron death. In the present paper, starting from some of the genes related to familial ALS, we overview and discuss their potential role in modifying of the physiological clearance of altered proteins and organelles in motor neurons. Special emphasis is placed on the role of autophagy, which seems to prevail as a protein clearing system over other multienzymatic pathways such as the proteasome within motor neurons. The evidence which links an altered autophagy to the onset of motor neuron death proposes that this biochemical pathway might represent a final common mechanism underlying both inherited and sporadic forms of ALS. In light of these findings we also analyze the potential significance of a novel association between ALS, altered autophagy, and mutations of nuclear proteins such as TAR-DNA-Binding Protein 43 and fused in sarcoma/translated in liposarcoma. Such an association appears to be critical since it is now well demonstrated that all sporadic and most familiar forms of ALS are characterized by altered deposition and mislocalization of TAR-DNA-Binding Protein 43. These novel insights into the pathogenesis of ALS may lead to the identification of novel strategies to promote motor neuron survival.
authors.affiliation: Department of Neuroscience, Clinical Neurology, University of Pisa, Pisa, Italy.
authors.forename: Livia
authors.initials: L
authors.lastname: Pasquali
authors.forename: Riccardo
authors.initials: R
authors.lastname: Ruffoli
authors.forename: Federica
authors.initials: F
authors.lastname: Fulceri
authors.forename: Sara
authors.initials: S
authors.lastname: Pietracupa
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: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D001343:Autophagy / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D009410:Nerve Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*