Abstract
One of the key pathways implicated in amyotrophic lateral sclerosis (ALS) pathogenesis is abnormal RNA processing. Studies to date have focussed on defects in RNA stability, splicing, and translation, but this review article will focus on the largely overlooked RNA processing mechanism of RNA trafficking, with particular emphasis on the importance of glia. In the central nervous system (CNS), oligodendrocytes can extend processes to myelinate and metabolically support up to 50 axons and astrocytes can extend processes to cover up to 100,000 synapses, all with differing local functional requirements. Furthermore, many of the proteins required in these processes are large, aggregation-prone proteins which would be difficult to transport in their fully translated, terminally-folded state. This, therefore, highlights a critical requirement in these cells for local control of protein translation, which is achieved through specific trafficking of mRNAs to each process and local translation therein. Given that a large number of RNA-binding proteins have been implicated in ALS, and RNA-binding proteins are essential for trafficking mRNAs from the nucleus to glial processes for local translation, RNA misprocessing in glial cells is a likely source of cellular dysfunction in ALS. To date, neurons have been the focus of ALS research, but an intrinsic deficit in glia, namely astrocytes and oligodendrocytes, could have an additive effect on declining neuronal function in ALS. This review article aims to highlight the key evidence that supports the contention that RNA trafficking deficits in astrocytes and oligodendrocytes may contribute to in ALS.
Highlights
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized pathologically by the accumulation of cytoplasmic inclusions in affected neurons and glial cells that, in 97%–98% of cases, stain positive for TAR-DNA binding protein 43 (TDP-43; Neumann et al, 2006)
Their involvement ranges from an impaired ability of the RNA granule to sufficiently aid in localization, translation and stability of the mRNAs, to the formation of stress granules, all of which have been implicated in ALS and can initiate a cascade of downstream events predicted to play a role in neuronal decline (Fan and Leung, 2016)
We propose that the proteinopathy present in the majority of ALS patients could be impacting on local translation of mRNAs, thereby hindering the normal function of glia in patients with ALS and FTD, potentially contributing to neuronal decline and disease progression
Summary
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized pathologically by the accumulation of cytoplasmic inclusions in affected neurons and glial cells that, in 97%–98% of cases, stain positive for TAR-DNA binding protein 43 (TDP-43; Neumann et al, 2006). TDP-43, like many of the proteins that have been associated with ALS pathogenesis, is a DNA and RNA-binding protein, implicating impaired RNA processing as a possible mechanism of disease. Regulatory proteins bind to mRNA transcripts to aid in localization, translation and stability, whilst playing important roles in transcription, alternative splicing and nuclear export
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