title: Cell to cell spreading of misfolded proteins as a therapeutic target in motor neuron disease.
abstract: Despite a number of genetic mutations and molecular mechanisms are recognized to participate in amyotrophic lateral sclerosis (ALS), such a devastating neurological disorder still lacks a substantial cure. The present manuscript rather than a general overview of potential therapeutic approaches focuses on novel research findings detailing novel molecular mechanisms which appear to be promising for developing future ALS therapeutics. A special emphasis is given to the abnormal autophagy status and to those autophagy substrates which aggregate in the form of misfolded proteins. In fact, as reviewed in the first part of the manuscript, altered autophagy pathway is present in most genetic mutations responsible for familial ALS. These mutations impair clearance of autophagy substrates, which determines accumulation of giant altered mitochondria and misfolded proteins. Therefore, a considerable piece of the review is dedicated to unconventional processing of misfolded proteins leading to unconventional protein secretions which may underlie a prionoid cellto- cell spreading of ALS neuropathology. The intimate mechanisms regulating these steps are analyzed in order to comprehend which potential therapeutic targets might be considered in future studies. At the same time, negative findings concerning recent trials are explained in light of novel disease mechanisms. In the final part of the review the replacement therapy with focal stem cells implantation is discussed in relationship with toxic mechanisms operating in the intercellular space of the spinal cord and motor-related areas.
authors.forename: Livia
authors.initials: L
authors.lastname: Pasquali
authors.forename: Paola
authors.initials: P
authors.lastname: Lenzi
authors.forename: Francesca
authors.initials: F
authors.lastname: Biagioni
authors.forename: Gabriele
authors.initials: G
authors.lastname: Siciliano
authors.affiliation: Department of Translational Research in Medicine and Surgery University of Pisa, Via Roma 55, 56126, Pisa, Italy. f.fornai@med.unipi.it.
authors.forename: Francesco
authors.initials: F
authors.lastname: Fornai
mesh_terms: D001343:Autophagy; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D016472:Motor Neuron Disease / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D066263:Protein Aggregation, Pathological; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D033581:Stem Cell Transplantation
chemical_list: D017127:Glycation End Products, Advanced; D011506:Proteins