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. 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.

Physiological functions and pathobiology of TDP‐43 and FUS/TLS proteins

“…Similar to other mRNA transport RBPs in neuronal cells, such as Staufen and FMPR, FUS/TLS is transported into dendrites not only in association with microtubules but also with actin filaments and the molecular motor myosin-V whose role is to specifically sort RNA granules into dendrites Yoshimura et al 2006). More recently, FUS/TLS, TDP-43, and SOD1 have also been shown to be transported to neurite terminals by a mechanism that involves endoplasmic reticulum tubules and the neurofilament cytoskeleton (Muresan and Ladescu Muresan 2016).…”

“…). More recently, FUS/TLS, TDP‐43, and SOD1 have also been shown to be transported to neurite terminals by a mechanism that involves endoplasmic reticulum tubules and the neurofilament cytoskeleton (Muresan and Ladescu Muresan ).…”

Formation of Toxic Oligomeric Assemblies of RNA-binding Protein: Musashi in Alzheimer’s disease

“…Alzheimer’s disease (AD) is the most common neurodegenerative disorder associated with structural and functional alterations of brain cells causing progressive deterioration of memory and other cognitive functions. Recent studies demonstrate that several neurodegenerative diseases, including AD, exhibit RNA-binding proteins (RBPs) pathologies, such as TAR DNA- binding protein (TDP-43), fused in sarcoma (FUS), superoxide dismutase 1 (SOD1) and T-interacting antigen-1 (TIA-1), highlighting the role of RBPs in neurodegeneration [ 12 , 34 , 40 ]. Musashi proteins belong to a group of RBPs that regulate the translation of target mRNAs during neuronal development, originally observed to regulate asymmetric stem cell division in Drosophila melanogaster [ 42 ].…”

“…In the past few years, several different RBPs have been identified demonstrating their altered functions and aggregation properties in neurodegenerative diseases [ 12 ], among which TDP-43, FUS and TIA-1 are extensively studied (Fig. 1 ) [ 11 , 40 , 47 – 49 ]. Abnormal accumulation of tau, a micro-tubule binding protein pathologically characterizes a group of neurodegenerative diseases, known as tauopathies [ 10 ].…”

A Human‐Based Functional NMJ System for Personalized ALS Modeling and Drug Testing

“…For example, soluble Amyloid β precursor protein (sAPP), FUS, TDP‐43, and SOD1 all share the same axonal transportation mechanisms. [ 44 ] So the comorbidity of AD and ALS in the patient harboring the FUS R522A mutation may reciprocately aggravate each disease and caused the early onset of ALS in this patient, although the MN phenotype alone is not as severe as the two other ALS lines. As in Table 1, each mutant displayed a unique phenotype “signature.” Correspondently, DP treatment caused different levels of effectiveness and parameter preference in the different ALS mutants.…”