TDP-43 and NEAT long non-coding RNA: Roles in neurodegenerative disease

Abstract

Understanding and ameliorating neurodegenerative diseases represents a key challenge for supporting the health span of the aging population. Diverse protein aggregates have been implicated in such neurodegenerative disorders, including amyloid-β, α-synuclein, tau, fused in sarcoma (FUS), and transactivation response element (TAR) DNA-binding protein 43 (TDP-43). Recent years have seen significant growth in our mechanistic knowledge of relationships between these proteins and some of the membrane-less nuclear structures that fulfill key roles in the cell function. These include the nucleolus, nuclear speckles, and paraspeckles. The ability of macromolecular protein:RNA complexes to partition these nuclear condensates through biophysical processes that involve liquid–liquid phase separation (LLPS) has also gained attention recently. The paraspeckle, which is scaffolded by the architectural long-non-coding RNA nuclear enriched abundant transcript 1 (NEAT1) plays central roles in RNA processing and metabolism and has been linked dynamically to TDP-43. In this mini-review, we outline essential early and recent insights in relation to TDP-43 proteinopathies. We then appraise the relationships between TDP-43 and NEAT1 in the context of neuronal paraspeckles and neuronal stress. We highlight key areas for investigation based on recent advances in our understanding of how TDP-43 affects neuronal function, especially in relation to messenger ribosomal nucleic acid (mRNA) splicing. Finally, we offer perspectives that should be considered for translational pipelines in order to improve health outcomes for the management of neurodegenerative diseases.

TDP-43 Epigenetic Facets and Their Neurodegenerative Implications

“…The protective role of NEAT1 against TDP-43 toxicity has been attributed to a sponge-like action and proposed to bind and neutralize the excess of TDP-43 [ 209 ]. The role of NEAT1 in the regulation of TDP-43 and the roles of this particular interaction in neurodegenerative diseases have been recently and specifically reviewed [ 210 ]. It is so far not known if the sequestration of TDP-43 by NEAT1 has an impact on its localization, abundance, and function at chromatin.…”

Proteomics Elucidating Physiological and Pathological Functions of TDP-43

“…Conversely, upon accumulation of TDP-43 the major long isoform NEAT1_1 was found up-regulated and appeared to counteract pathological effects of TDP-43 [115]. TDP-43 interplay with NEAT1 therefore seems to be an important regulatory mechanism influencing cellular viability via paraspeckles, nuclear domains mediating RNA processing and metabolism [116].…”

Disrupting pathologic phase transitions in neurodegeneration

“…While TDP-43 typically resides in the nucleus, it also shuttles from the nucleus to the cytoplasm and is found mislocalized to the cytoplasm of diseased neurons ( 40 , 128 ). Notably, TDP-43 is a component of several RNP granules, including paraspeckles, nuclear stress bodies, and RNA transport granules in neurons ( 12 , 69 , 130 ).…”