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.
Highlights
The first descriptions of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) were provided in the late 19th century by Jean-Martin Charcot (1874) and Arnold Pick (1892), respectively, highlighting the defining features of both diseases
It is clear that transactivation response (TAR) DNA-binding protein-43 KDa (TDP-43) affects the structures and functions of dendritic spines, the exact mechanisms remain to be resolved
The enrichment of TDP-43 and fused in sarcoma (FUS) binding to 3′-UTR of cytosolic mRNAs further suggests that TDP-43 and FUS could influence the fates of RNA beyond their nuclear actions
Summary
The first descriptions of ALS and FTD were provided in the late 19th century by Jean-Martin Charcot (1874) and Arnold Pick (1892), respectively, highlighting the defining features of both diseases. Given the evidence that TDP-43 and FUS bind to many RNA targets important for synaptic function [22,23,24,25,26] (Figure 2), it is conceivable that TDP-43 and FUS can regulate synaptic plasticity through RNA transport and local translation, and dysfunction of TDP-43 or FUS may cause defects in synaptic function which will affect the health of neurons This “synaptic toxicity” hypothesis, in which synaptic damage is among the early events that eventually lead to neurodegeneration, has been proposed for Alzheimer’s disease [27,28,29] and Parkinson’s disease [30] and is gaining recognition in the context of FTD and ALS [31, 32]. The key functions will be highlighted in this review, with an emphasis on how TDP-43 and FUS may regulate synaptic function
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