Amyotrophic Lateral Sclerosis (ALS): Stressed by Dysfunctional Mitochondria-Endoplasmic Reticulum Contacts (MERCs)

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease for which there is currently no cure. Progress in the characterization of other neurodegenerative mechanisms has shifted the spotlight onto an intracellular structure called mitochondria-endoplasmic reticulum (ER) contacts (MERCs) whose ER portion can be biochemically isolated as mitochondria-associated membranes (MAMs). Within the central nervous system (CNS), these structures control the metabolic output of mitochondria and keep sources of oxidative stress in check via autophagy. The most relevant MERC controllers in the ALS pathogenesis are vesicle-associated membrane protein-associated protein B (VAPB), a mitochondria-ER tether, and the ubiquitin-specific chaperone valosin containing protein (VCP). These two systems cooperate to maintain mitochondrial energy output and prevent oxidative stress. In ALS, mutant VAPB and VCP take a central position in the pathology through MERC dysfunction that ultimately alters or compromises mitochondrial bioenergetics. Intriguingly, both proteins are targets themselves of other ALS mutant proteins, including C9orf72, FUS, or TDP-43. Thus, a new picture emerges, where different triggers cause MERC dysfunction in ALS, subsequently leading to well-known pathological changes including endoplasmic reticulum (ER) stress, inflammation, and motor neuron death.

Current Concepts on Genetic Aspects of Mitochondrial Dysfunction in Amyotrophic Lateral Sclerosis

“…Among proteins recognized as targets for mutant C9orf72, TDP-43 or FUS are valosin containing protein (VCP) and vesicle-associated membrane protein-associated protein B (VAPB). Interestingly, those proteins, coded by ALS-associated genes VCP and VAPB , are responsible for normal functioning of mitochondria-endoplasmic reticulum contacts (MERCs), structures that are controlling mitochondrial metabolism and oxidative stress level [ 65 ].…”

“…Sigma non-opioid intracellular receptor 1 (SIGMAR1) is another MERC-associated chaperon, responsible for maintaining calcium signaling [ 65 ]. Mutations in gene SIGMAR1 are described in autosomal recessive juvenile ALS, as well as in distal neuropathies [ 84 ].…”

The Link between VAPB Loss of Function and Amyotrophic Lateral Sclerosis

“…Disruption of ER-mitochondria contacts as a common theme in neurodegenerative disease, including ALS, is attracting increasing interest and could represent a point of convergence of pathological events triggered by different initial insults to neurons [34,64,[143][144][145][146]. This fascinating subject is discussed in greater detail in another review of this special issue [147] PI4P is one of the two most abundant phosphoinositides, a family of signalling lipids that are generated by phosphorylation of the inositol headgroup of phosphatidylinositol (PI) and that act by recruiting specific proteins to the cytosolic surface of membranes. Because of the restricted distribution of the kinases, which generate them, the phosphatases, which consume them, and lipid transport proteins (LTPs) which transport them, each phosphoinositide is specifically distributed to single compartments or subsets thereof, thereby contributing to the definition of organelle identity (reviewed in [148]).…”

Yeast Models and Molecular Mechanisms of Neurodegenerative Diseases

“…SGs containing Rpg1-3 have been characterized; they are formed at a lower temperature than those containing wild-type Rpg1 and are more stable. Interestingly, the delayed disassembly of these SGs is reversed by the overproduction of TDP-43, which is a human protein associated with ALS, a disease connected with the dysfunction of mitochondrion-ER contacts (MERCs) [16]. Disease-causing amino acid residue substitutions in TDP-43 result in the sequestration of the mutant TDP-43 protein, together with its interacting partners, in cytoplasmic aggregates [16].…”

“…Interestingly, the delayed disassembly of these SGs is reversed by the overproduction of TDP-43, which is a human protein associated with ALS, a disease connected with the dysfunction of mitochondrion-ER contacts (MERCs) [16]. Disease-causing amino acid residue substitutions in TDP-43 result in the sequestration of the mutant TDP-43 protein, together with its interacting partners, in cytoplasmic aggregates [16]. These aggregates and SGs could be cytotoxic and contribute to the death of neurons [17].…”