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

Virgil Muresan, Zoia Ladescu Muresan

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

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. Summary: 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. Key Messages: 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.Background: Effective therap.

Original languageEnglish (US)
Pages (from-to)55-61
Number of pages7
JournalNeurodegenerative Diseases
Volume16
Issue number1-2
DOIs
StatePublished - Feb 1 2016

All Science Journal Classification (ASJC) codes

  • Neurology
  • Clinical Neurology

Keywords

  • Alzheimer's disease
  • Amyloid-β precursor protein
  • Amyotrophic lateral sclerosis
  • Converging mechanisms of neurodegenerative diseases
  • Endoplasmic reticulum
  • FUS
  • Motor neurons
  • Neurofilaments
  • SOD1
  • TDP-43

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