Proteinopathies as Hallmarks of Impaired Gene Expression, Proteostasis and Mitochondrial Function in Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disease characterized by progressive degeneration of upper and lower motor neurons. As with the majority of neurodegenerative diseases, the pathological hallmarks of ALS involve proteinopathies which lead to the formation of various polyubiquitylated protein aggregates in neurons and glia. ALS is a highly heterogeneous disease, with both familial and sporadic forms arising from the convergence of multiple disease mechanisms, many of which remain elusive. There has been considerable research effort invested into exploring these disease mechanisms and in recent years dysregulation of RNA metabolism and mitochondrial function have emerged as of crucial importance to the onset and development of ALS proteinopathies. Widespread alterations of the RNA metabolism and post-translational processing of proteins lead to the disruption of multiple biological pathways. Abnormal mitochondrial structure, impaired ATP production, dysregulation of energy metabolism and calcium homeostasis as well as apoptosis have been implicated in the neurodegenerative process. Dysfunctional mitochondria further accumulate in ALS motor neurons and reflect a wider failure of cellular quality control systems, including mitophagy and other autophagic processes. Here, we review the evidence for RNA and mitochondrial dysfunction as some of the earliest critical pathophysiological events leading to the development of ALS proteinopathies, explore their relative pathological contributions and their points of convergence with other key disease mechanisms. This review will focus primarily on mutations in genes causing four major types of ALS (C9ORF72, SOD1, TARDBP/TDP-43, and FUS) and in protein homeostasis genes (SQSTM1, OPTN, VCP, and UBQLN2) as well as sporadic forms of the disease. Finally, we will look to the future of ALS research and how an improved understanding of central mechanisms underpinning proteinopathies might inform research directions and have implications for the development of novel therapeutic approaches.

Biomarkers in Human Peripheral Blood Mononuclear Cells: The State of the Art in Amyotrophic Lateral Sclerosis

“…Many neurodegenerative diseases, including ALS, are considered proteinopathies, usually represented by the accumulation of protein aggregates [ 112 ]. Moreover, protein accumulation can be exploited for the discovery of new biomarkers, represented by evaluating the protein expression level in cerebrospinal fluid (CSF), plasma and PBMCs of ALS patients [ 42 ].…”

“…Many other proteins are involved in ALS [ 112 ]. For example, Kuźma-Kozakiewicz and colleagues focused their work on the expression of motor proteins involved in both the anterograde and the retrograde transport in PBMCs obtained from SALS patients, healthy control subjects and other neurological disease(s) patients [ 82 ].…”

Mechanistic Insights of Mitochondrial Dysfunction in Amyotrophic Lateral Sclerosis: An Update on a Lasting Relationship

“…Accordingly, Singh et al identified similar mitochondrial dysfunction in both sALS and fALS human iPSCs-derived MNs [ 155 ]. However, differences in mitochondrial pathophysiology between sALS and fALS have been reported in other iPSCs models [ 107 , 150 , 151 ]. Choi et al investigated how the blockade of the PP1-DRP1 cascade effectively prevented mitochondrial defects and subsequent cell death in iPSC-derived human MNs [ 107 ].…”

Is Dutasteride a Therapeutic Alternative for Amyotrophic Lateral Sclerosis?

“…In addition, much of the animal-model research focuses on mutations in the TARDBP transactive response DNA-binding protein gene (TDP-43) associated with approximately 5% of fALS cases [ 53 ], sarcoma fusion protein (fused in sarcoma (FUS)) and valosin-containing protein (VCP), due to its link to fALS and diseases of a similar nature [ 52 , 54 ].…”

“…In particular, alterations in the RNA recognition domain (RRM1) of TDP-43, induced by OS, can promote its aggregation and incorrect localization in the cytoplasm [ 60 ]. These abnormal protein aggregates are the most representative in ALS disease [ 54 , 61 , 62 ].…”