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Review
. 2020 Aug 25;10(3):101.
doi: 10.3390/jpm10030101.

Molecular and Cellular Mechanisms Affected in ALS

Laura Le Gall  1   2 , Ekene Anakor  1 , Owen Connolly  1 , Udaya Geetha Vijayakumar  1 , William J Duddy  1 , Stephanie Duguez  1
Affiliations
Review

Molecular and Cellular Mechanisms Affected in ALS

Laura Le Gall et al. J Pers Med. .

Abstract

Amyotrophic lateral sclerosis (ALS) is a terminal late-onset condition characterized by the loss of upper and lower motor neurons. Mutations in more than 30 genes are associated to the disease, but these explain only ~20% of cases. The molecular functions of these genes implicate a wide range of cellular processes in ALS pathology, a cohesive understanding of which may provide clues to common molecular mechanisms across both familial (inherited) and sporadic cases and could be key to the development of effective therapeutic approaches. Here, the different pathways that have been investigated in ALS are summarized, discussing in detail: mitochondrial dysfunction, oxidative stress, axonal transport dysregulation, glutamate excitotoxicity, endosomal and vesicular transport impairment, impaired protein homeostasis, and aberrant RNA metabolism. This review considers the mechanistic roles of ALS-associated genes in pathology, viewed through the prism of shared molecular pathways.

Keywords: MND; RNA metabolism; autophagy; axonal transport; endocytosis; excitotoxicity; mitochondria dysfunction; oxidative stress; secretion.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Oxidative stress, mitochondrial dysfunction, axonal transport, and glutamate excitotoxicity in amyotrophic lateral sclerosis (ALS). An increase in oxidative stress can result from defects in detoxifying pathways. Such defects include the loss of SOD1 function, aberrant DNA damage repair machinery, or a decrease in expression of antioxidant genes affecting the NRF2-ARE pathway. Oxidative stress can also be increased by the stimulation of ROS production via increased NADPH oxidase activity or from disrupted mitchondrial respiratory chain activity. Mitochondrial activity can be affected by several ALS mutations, such as those leading to the accumulation of protein aggregates, or to decreased mitochondrial biogenesis and transport, or to increased cytosolic Ca2+ (as observed when glutamate receptor activity is stimulated or when the Ca2+-buffering capacity is decreased). Consequently a disruption of the mitochondrial respiratory chain will lead to an increase in ROS production and, thus, to an accumulation of oxidized proteins, lipids, DNA, and RNA. Oxidative damage occurring over time may then stimulate apoptotosis and, thus, cell death. Defective axonal transport affects not only the mitochondria but, also, the transport of other proteins and RNA, with consequences on the axon structure and function being accompanied by neurofilament accumulation. Defective glutamate uptake by astrocytes, and/or a defect in glutamate receptor clearance or in AMPA or GABA receptors, can lead to increased Ca2+ permeability and can impact the post-synaptic hyperexcitability and mitochondrial function. ARE: antioxidant response element, AMPA2: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor 2, ATXN2: ataxin 2, Bcl2: B-cell lymphoma 2, C9orf72: Chromosome 9 open reading frame 72, C21orf2: Chromosome 21 open reading frame 7, CHCHD10: coiled-coil helix coiled-coil helix domain-containing 10, DCTN1: Dynactin 1, EEAT2: Excitatory amino acid transporter, ER: endoplasmic reticulum, FUS: Fused in Sarcoma, GABA: gamma-Aminobutyric acid, GlyR: glycine receptor, GlyT: glycine transporter, KIF5A: Kinesin heavy-chain isoform 5A, MAM: Mitochondria-associated ER membranes, NEFH: heavy-weighted neurofilaments, NEK1: (NIMA)-related kinase 1, NMDA: N-methyl-D-aspartate receptor, NRF2: Nuclear erythroid 2-Related Factor, PFN1: profilin-I, PTPIP51: Protein tyrosine phosphatase-interacting protein 51, SETX: senataxin, SOD: Superoxide dismutase 1, SPG11: Spatacsin, TDP-43: TAR DNA-binding protein 43, VAPB: vesicle-associated membrane protein-associated protein B, VCP: valosin-containing protein, and ROS: reactive oxygen species.
Figure 2
Figure 2
Protein homeostasis dysregulation. Dysregulated protein homeostasis is mediated by multiple pathways encompassing defects in autophagy, the dysregulated ubiquitin-proteasome system (UPS), endo-lysosomal pathway disruptions, or endoplasmic reticulum (ER) stress. The presence of misfolded proteins activates endoplasmic reticulum-associated protein degradation (ERAD), leading to proteasome-mediated degradation to avoid misfolded protein accumulations in the ER lumen and subsequent ER stress. Several ALS-associated gene mutations induce proteasome-mediated toxicity via the sequestration of ubiquilin and chaperone proteins involved in the UPS pathway. The proteolytic activity of the proteasome has also been demonstrated to be targeted by gene mutations in ALS. The autophagic pathway involves the formation and maturation of phagophores that engulf selected transported-cargo and form autophagosomes. Fusion with the lysosome enables the degradation of autophagosome contents. Defects in autophagy initiation and expansion, dysregulated phagophore formation, and/or impaired cargo transport are observed in ALS patients. Mutations in ALS-associated genes also cause defects in mitophagy, a specific form of autophagy. Defects in the endolysosomal have been associated with ALS gene mutations, including defective endolysosomal trafficking and altered lysosomal hoemostasis and degradation. Defects in the autophagy/lysosomal pathway may affect vesicle secretion. Genes implicated in dysregulated protein homeostasis are indicated in red. ER: endoplasmic reticulum, ERAD: endoplasmic reticulum-associated protein degradation, ALS2: Alsin, C9orf72: Chromosome 9 open reading frame 72, CCNF: Cyclin F, CHCHD10: coiled-coil helix coiled-coil helix domain-containing 10, CHMP2B: chromatin-modifying protein 2B, DCTN1: Dynactin 1, FIG4: Phosphoinositide 5-phosphatase, FUS: Fused in Sarcoma, MATR3: matrin 3, MVB: Multivesicular bodies, OPTN: Optineurin, SOD1: Superoxide dismutase 1, SPG11: Spatacsin, TDP-43: TAR DNA-binding protein 43, TBK1: TANK-binding kinase-1, UBQLN2: Ubiquilin-2, VAPB: vesicle-associated membrane protein-associated protein B, and VCP: valosin-containing protein.
Figure 3
Figure 3
RNA and miRNA biogenesis defects in ALS. Many processes in RNA and miRNA pathways are disrupted in ALS patients, including transcription defects, alternate splicing events, miRNA biogenesis, and nucleus-cytosol transport impairment. RNA metabolism defects are particularly relevant in ALS pathogenesis, since TDP-43 and FUS are both well-known ALS-associated genes involved in RNA processing. Both FUS and TDP-43-mutated proteins mislocalize to the cytoplasm of ALS motor neurons, leading to a probable loss and/or toxic gain-of-function of these proteins. ANG: Angiogenin, ATXN2: Ataxin-2, C9orf72: Chromosome 9 open reading frame 72, DCTN1: Dynactin 1, eIF2α: Eukaryotic translation initiation factor 2A, ELP3: Elongator protein 3, FUS: Fused in Sarcoma, G3BP1: Ras GTPase-activating protein-binding protein 1, hNRNPA1: Heterogeneous nuclear ribonucleoprotein A1, hnRNPA2B1: Heterogeneous nuclear ribonucleoprotein A2B1, MATR3: matrin 3, NEFH: Neurofilament heavy subunit, PABP1: Polyadenylate-binding protein 1, PFN1: Profilin, SETX: Senataxin, SOD1: Superoxide dismutase 1, TDP-43: TAR DNA-binding protein 43, and TIA-1: TIA1 Cytotoxic Granule-Associated RNA-Binding Protein.
Figure 4
Figure 4
Summary of the different molecular and cellular mechanisms involved in ALS pathogenesis. Among the most studied and well-established pathways are: oxidative stress, mitochondrial dysfunction, axonal transport, glutamate excitotoxicity, endosomal and vesicle secretions, protein homeostasis, and RNA metabolism. One pathway may lead to another, exacerbating the disruption of cellular homeostasis. The disruption of these pathways can lead to microglia activation, neuroinflamation, astrocytosis, and, ultimately, to motor neuron death and muscle denervation.
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References

    1. Arthur K.C., Calvo A., Price T.R., Geiger J.T., Chiò A., Traynor B.J. Projected increase in amyotrophic lateral sclerosis from 2015 to 2040. Nat. Commun. 2016;7:12408. doi: 10.1038/ncomms12408. - DOI - PMC - PubMed
    1. Ragagnin A.M.G., Shadfar S., Vidal M., Jamali M.S., Atkin J.D. Motor Neuron Susceptibility in ALS/FTD. Front. Neurosci. 2019;13:532. doi: 10.3389/fnins.2019.00532. - DOI - PMC - PubMed
    1. Nicaise C., Mitrecic D., Pochet R. Brain and spinal cord affected by amyotrophic lateral sclerosis induce differential growth factors expression in rat mesenchymal and neural stem cells. Neuropathol. Appl. Neurobiol. 2011;37:179–188. doi: 10.1111/j.1365-2990.2010.01124.x. - DOI - PubMed
    1. Gibbons C., Pagnini F., Friede T., Young C.A. Treatment of fatigue in amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database Syst. Rev. 2018 doi: 10.1002/14651858.CD011005.pub2. - DOI - PMC - PubMed
    1. Turner M.R., Al-Chalabi A., Chio A., Hardiman O., Kiernan M.C., Rohrer J.D., Rowe J., Seeley W., Talbot K. Genetic screening in sporadic ALS and FTD. J. Neurol. Neurosurg. Psychiatry. 2017;88:1042–1044. doi: 10.1136/jnnp-2017-315995. - DOI - PMC - PubMed

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