title: Shared Molecular Mechanisms in Alzheimer's Disease and Amyotrophic Lateral Sclerosis: Neurofilament-Dependent Transport of sAPP, FUS, TDP-43 and SOD1, with Endoplasmic Reticulum-Like Tubules.
abstract: BACKGROUND
  Amyotrophic lateral sclerosis (ALS), a debilitating neurodegenerative disorder of the motor neurons, leads to the disorganization of the neurofilament (NF) cytoskeleton and - ultimately - the deterioration of the neuromuscular junction. Some familial cases of ALS are caused by mutated FUS, TDP-43 or SOD1; it is thought that the mutated proteins inflict pathology either by gain or loss of function. The proper function of the neuromuscular junction requires sAPP, a soluble proteolytic fragment of the amyloid-β precursor protein (APP) - a transmembrane protein implicated in the pathology of Alzheimer's disease (AD). Whether sAPP, FUS, TDP-43 and SOD1 are mechanistically linked in a common pathway deregulated in both AD and ALS is not known.
  
  
  CONCLUSIONS
  We show that sAPP, TDP-43, FUS and SOD1 are transported to neurite terminals by a mechanism that involves endoplasmic reticulum (ER)-like tubules and requires peripherin NFs. The transport of these proteins, and the translocation of the ER protein reticulon 4 (Rtn4) into neurites was studied in CAD cells, a brainstem-derived neuronal cell line highly relevant to AD and ALS. We show that a significant fraction of sAPP is generated in the soma and accumulates in a juxtanuclear ER subdomain. In neurites, sAPP localizes to Rtn4-positive ER-like tubules that extend from the soma into the growth cone and colocalizes with peripherin NFs. Knocking down peripherin disrupts the NF network and diminishes the accumulation of sAPP, TDP-43, FUS, SOD1 and Rtn4 at terminals.
  
  
  CONCLUSIONS
  We propose that the impediment of a common, ER-mediated mechanism of transport of sAPP, TDP-43, FUS and SOD1, caused by a disrupted NF network, could be part of the mechanisms leading to AD and ALS.
authors.affiliation: Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, N.J., USA.
authors.forename: Virgil
authors.initials: V
authors.lastname: Muresan
authors.forename: Zoia
authors.initials: Z
authors.lastname: Ladescu Muresan
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D001692:Biological Transport / Q000502:physiology; D001933:Brain Stem / Q000378:metabolism; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D020439:Growth Cones / Q000378:metabolism; D006801:Humans; D007382:Intermediate Filaments / Q000378:metabolism; D009185:Myelin Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D000070798:Nogo Proteins; D064531:Peripherins / Q000378:metabolism; D034702:RNA-Binding Protein FUS / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D004268:DNA-Binding Proteins; C000599550:FUS protein, human; D009185:Myelin Proteins; D000070798:Nogo Proteins; C578994:PRPH protein, human; D064531:Peripherins; D034702:RNA-Binding Protein FUS; C000603199:RTN4 protein, human; C000606290:SOD1 protein, human; C000598624:TARDBP protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1