Stress Granule Dysregulation in Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with no current cure. ALS causes degeneration of both upper and lower motor neurons leading to atrophy of the innervating muscles and progressive paralysis. The exact mechanism of the pathology of ALS is unknown. However, 147 genes have been identified that are causative, associated with, or modify disease progression. While the causative mechanism is unknown, a number of pathological processes have been associated with ALS. These include mitochondrial dysfunction, protein accumulation, and defects in RNA metabolism. RNA metabolism is a complicated process that is regulated by many different RNA-binding proteins (RBPs). A small defect in RNA metabolism can produce results as dramatic as determining cell survival. Stress granules (SGs) control RNA translation during stressed conditions. This is a protective reaction, but in conditions of chronic stress can become pathogenic. SGs are even hypothesized to act as a seeding mechanism for the pathological aggregation of proteins seen in many neurodegenerative diseases, including TAR DNA-binding protein 43 (TDP-43) in ALS. In this review, we will be summarizing the current findings of SG pathology in ALS. We also focus on the role of SG dysregulation in protein aggregate formation and mitochondrial dysfunction. In addition, we outline therapeutic strategies that target SG components in ALS.

Amyotrophic Lateral Sclerosis Genes in Drosophila melanogaster

“…SGs play a crucial role in RNA metabolism, notably in translation inhibition through phosphorylation of eukaryotic initiation factor 2α (eIF2α). Originally protective, under chronic stress, the presence of SGs could lead to pathological conditions (for reviews, see [ 214 , 215 , 216 ]). Thus, SGs could act as a seeding mechanism that result in accumulation of RBPs.…”

RNA-Binding Proteins and the Complex Pathophysiology of ALS

“…Since the first identification of superoxide dismutase 1 ( SOD1 ) as an ALS causative gene in 1993 [ 7 ], significant research efforts and advanced genetic approaches have identified mutations in more than 30 genes that cause ALS and frontotemporal dementia (FTD) [ 15 , 16 , 17 , 18 ]. In addition, 147 different gene mutations found in many different pathways have been shown to contribute to the pathogenesis of ALS [ 19 , 20 ]. Although sporadic ALS cases are much more common than familial ALS cases, a portion can be explained by ALS-causing mutations in genes.…”

“…The most common ALS- and FTD-causing gene mutation is a GGGGCC hexanucleotide repeat expansion in the first intron region of the chromosome 9 open reading frame 72 ( C9orf72 ) gene [ 34 , 35 ]. ALS and FTD patients display several hundred to a few thousand copies of the GGGGCC repeat in the C9orf72 gene [ 34 ], and the C9orf72 repeat expansion’s toxicity increases with age, repeat length, and expression level [ 19 , 36 ]. Repeat-containing transcripts of the mutated C9orf72 gene can form RNA foci enriched with RNA-binding proteins in induced pluripotent stem cell (iPSC)-derived neurons from ALS and FTD patients, as well as in motor neurons of C9orf72-ALS patients [ 37 , 38 , 39 , 40 ].…”

“…Repeat-containing transcripts of the mutated C9orf72 gene can form RNA foci enriched with RNA-binding proteins in induced pluripotent stem cell (iPSC)-derived neurons from ALS and FTD patients, as well as in motor neurons of C9orf72-ALS patients [ 37 , 38 , 39 , 40 ]. Even though conflicting evidence remains about the mechanisms of toxicity of C9orf72 mutations [ 19 , 36 , 41 ], RNA foci are believed to sequestrate bound RNA-binding proteins and result in toxicity [ 42 ]. Dipeptide repeat (DPR), glycine-alanine (GA), glycine-arginine (GR), proline-arginine (PR), proline-alanine (PA), and glycine-proline (GP) are generated through repeat-associated non-ATG translation from hexanucleotide repeat expansion-containing transcripts [ 43 , 44 , 45 , 46 ].…”

“…ALS-associated FUS mutants that show the mislocalization and formation of cytoplasmic aggregates inhibit the splicing of minor introns by the sequestration of U11 and U12 small nuclear ribonucleoprotein (snRNP) [ 68 ]. Studies on TARDBP and FUS mislocalization show that either of these can affect the entire nucleo-cytoplasmic transport capability of the cells [ 19 , 69 ]. Several studies have indicated that the physical interaction between repeat RNA and RNA-binding proteins might also lead to the functional sequestration of RNA-binding proteins such as HNRNPA3, which plays a role in the cytoplasmic trafficking of RNA [ 70 , 71 ].…”