RNA-Binding Proteins and the Complex Pathophysiology of ALS

Abstract

Genetic analyses of patients with amyotrophic lateral sclerosis (ALS) have identified disease-causing mutations and accelerated the unveiling of complex molecular pathogenic mechanisms, which may be important for understanding the disease and developing therapeutic strategies. Many disease-related genes encode RNA-binding proteins, and most of the disease-causing RNA or proteins encoded by these genes form aggregates and disrupt cellular function related to RNA metabolism. Disease-related RNA or proteins interact or sequester other RNA-binding proteins. Eventually, many disease-causing mutations lead to the dysregulation of nucleocytoplasmic shuttling, the dysfunction of stress granules, and the altered dynamic function of the nucleolus as well as other membrane-less organelles. As RNA-binding proteins are usually components of several RNA-binding protein complexes that have other roles, the dysregulation of RNA-binding proteins tends to cause diverse forms of cellular dysfunction. Therefore, understanding the role of RNA-binding proteins will help elucidate the complex pathophysiology of ALS. Here, we summarize the current knowledge regarding the function of disease-associated RNA-binding proteins and their role in the dysfunction of membrane-less organelles.

Infectious RNA: Human Immunodeficiency Virus (HIV) Biology, Therapeutic Intervention, and the Quest for a Vaccine

“…RNA foci are believed to sequestrate bound RBPs and result in toxicity [97,98]. Many disease-related genes encode RBPs, where mutated gene products accumulate as aggregates disrupting cellular functions involved in RNA metabolism [99,100]. Mutations in the RBPs, TAR DNA (TARDBP), FUS RNA-binding protein (FUS), Ataxin 2 (ATXN2) as well as EWS RNA-binding proteins (EWSR1) and many more have been shown to greatly influence disease risks, e.g., amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FDT) [100].…”

RNA-Binding Proteins as Epigenetic Regulators of Brain Functions and Their Involvement in Neurodegeneration

“…These changes involve gene activation, but also changes in both the presynaptic and postsynaptic localized synthesis of proteins. The fine regulation of these processes depends on an efficient coordination of mRNA transport and metabolism, mostly managed by RBPs that, as discussed above, bind mRNAs and regulate their transport, stability, and translation, thus controlling proteostasis in response to synaptic activity [ 189 ]; aberrant translation could indeed affect synaptic plasticity and lead to neurodevelopmental disorders, such as autism spectrum disorders (ASDs) [ 217 , 218 ], and neurological pathologies, as well as neuropsychiatric disorders in adults, such as amyotrophic lateral sclerosis (ALS) [ 189 , 219 ].…”

RNA-binding proteins potentially regulate the alternative splicing of apoptotic genes during knee osteoarthritis progression

“…In the nucleus, some RNA-binding proteins (RBP) often function as AS regulators in a particular way in the disease course [ 13 , 14 ]. Functional disruptions in RBPs may be a major cause or consequence of a disease [ 15 , 16 ]. CUGBP Elav-like family (CELF) and muscleblind-like (MBNL) proteins are some examples of RBPs functioning as splicing regulators; they play vital roles in myotonic dystrophy by promoting opposite effects on the splice site or exon usage, affecting mRNA localization and stability in the cytoplasm [ 17 ].…”