RNA metabolism in neurodegenerative disease

Abstract

Aging-related neurodegenerative diseases are progressive and fatal neurological diseases that are characterized by irreversible neuron loss and gliosis. With a growing population of aging individuals, there is a pressing need to better understand the basic biology underlying these diseases. Although diverse disease mechanisms have been implicated in neurodegeneration, a common theme of altered RNA processing has emerged as a unifying contributing factor to neurodegenerative disease. RNA processing includes a series of distinct processes, including RNA splicing, transport and stability, as well as the biogenesis of non-coding RNAs. Here, we highlight how some of these mechanisms are altered in neurodegenerative disease, including the mislocalization of RNA-binding proteins and their sequestration induced by microsatellite repeats, microRNA biogenesis alterations and defective tRNA biogenesis, as well as changes to long-intergenic non-coding RNAs. We also highlight potential therapeutic interventions for each of these mechanisms.

Enzymatic degradation of RNA causes widespread protein aggregation in cell and tissue lysates

“…Altered RNA metabolism is a recurring theme in several neurodegenerative disorders (e.g. (Conlon & Manley, 2017;Liu et al, 2017;Ramaswami et al, 2013). In ALS and Frontotemporal Dementia, this is supported by both disease-causing genetic mutations in several RNA-binding proteins as well as by the generation of potentially toxic RNA species (Fratta et al, 2012;Haeusler et al, 2014;Kim et al, 2013;Kwiatkowski et al, 2009;Sreedharan et al, 2008;Vance et al, 2009).…”

SUMO1‐conjugation is altered during normal aging but not by increased amyloid burden

“…Consistent with this initial finding, our statistical analysis revealed a small group of candidate SUMO1 targets whose SUMOylation in vivo appeared to be altered during aging, but no SUMO1 candidate was identified to be altered during increased amyloid burden. Interestingly, these age‐related proteins are components of cellular signaling pathways with roles mainly in RNA processing, but also in protein folding and Ras signaling, many of which are known to play a role during aging (Balchin, Hayer‐Hartl & Hartl, 2016; Liu, Cali & Lee, 2017; Longo, 2004; Wang et al., 2011). Most of the nuclear proteins identified as age‐related SUMO1 candidate proteins are involved in the regulation of gene expression, chromatin remodeling, RNA processing, and protein folding.…”

Deregulation of RNA Metabolism in Microsatellite Expansion Diseases

“…For instance, RBP defects occur in both familial and sporadic cases of ALS/FTD [129, 130]. Mutations in TDP-43 and FUS/TLS genes result in abnormal aggregation of these proteins in neurons and are considered pathogenic for ALS/FTD.…”