Synaptic Paths to Neurodegeneration: The Emerging Role of TDP-43 and FUS in Synaptic Functions

Neural Plasticity
Shuo-Chien Ling

Abstract

TAR DNA-binding protein-43 KDa (TDP-43) and fused in sarcoma (FUS) as the defining pathological hallmarks for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), coupled with ALS-FTD-causing mutations in both genes, indicate that their dysfunctions damage the motor system and cognition. On the molecular level, TDP-43 and FUS participate in the biogenesis and metabolism of coding and noncoding RNAs as well as in the transport and translation of mRNAs as part of cytoplasmic mRNA-ribonucleoprotein (mRNP) granules. Intriguingly, many of the RNA targets of TDP-43 and FUS are involved in synaptic transmission and plasticity, indicating that synaptic dysfunction could be an early event contributing to motor and cognitive deficits in ALS and FTD. Furthermore, the ability of the low-complexity prion-like domains of TDP-43 and FUS to form liquid droplets suggests a potential mechanism for mRNP assembly and conversion. This review will discuss the role of TDP-43 and FUS in RNA metabolism, with an emphasis on the involvement of this process in synaptic function and neuroprotection. This will be followed by a discussion of the potential phase separation mechanism for forming RNP granules and pathological inclusions.

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Citations

Apr 11, 2020·Journal of Neurology, Neurosurgery, and Psychiatry·Emma L van der EndeUNKNOWN Genetic Frontotemporal Dementia Initiative (GENFI)
Jul 11, 2020·International Journal of Environmental Research and Public Health·Tian WangYi Xu
Jun 28, 2019·Frontiers in Cellular Neuroscience·Dhruva DeshpandeJens Michaelis
Jun 18, 2020·Frontiers in Molecular Neuroscience·Yuan Chao XueHonglin Luo
Nov 1, 2020·Proceedings of the National Academy of Sciences of the United States of America·Audrey Yi Tyan PengShuo-Chien Ling
Mar 18, 2021·Journal of Neuroscience Research·Karthik Krishnamurthy, Piera Pasinelli
May 4, 2021·Journal of Alzheimer's Disease : JAD·Vasily VorobyovAleksey A Ustyugov
Jun 4, 2021·Neurochemistry International·Joshua M MarcusShaida A Andrabi
Jul 2, 2021·Journal of Molecular Biology·Luigi I IconaruRichard W Kriwacki

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Methods Mentioned

BETA
HITS-CLIP
antisense oligonucleotides
transgenic
single-cell sequencing

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