TDP-43 in the spectrum of MND-FTLD pathologies

Abstract

The relationship between RNA-binding proteins, particularly TAR DNA binding protein 43 (TDP-43), and neurodegeneration is an important area of research. TDP-43 is involved in so many cellular processes that perturbation of protein homeostasis can lead to countless downstream effects. Understanding what leads to this disease-related protein imbalance and the resulting cellular and molecular effects will help to develop targets for disease intervention, whether it be prevention of protein accumulation, or addressing a secondary effect of protein accumulation. Here we review the current literature of TDP-43 and TDP-43 pathologies, the effects of TDP-43 overexpression and disruption of synaptic proteins through its binding of messenger RNA, leading to synaptic dysfunction. This review highlights some of the still-limited knowledge of the protein TDP-43 and how it can contribute to disease.

Figure 1. TDP-43 at the synapse

A) Under normal conditions, TDP-43 controls the expression of synaptic proteins such as synaptotagmin and synapsin I. It is present in postsynaptic dendrites, where it is involved in local protein translation. Normal TDP-43 expression is necessary for synaptic maintenance, neurotransmitter balance, and mitochondrial function. B) When TDP-43 is overexpressed, there is aberrant binding to its mRNA targets, leading to alterations in synaptic function. TDP-43 accumulates in the cytoplasm, forming protein aggregates. This aggregation can lead to loss of function or a toxic gain of function, which contribute to disease. TDP-43 overexpression is also associated with neurotransmitter imbalance, astrocyte dysfunction, and mitochondrial impairment. Maintenance of TDP-43 levels is crucial for normal synaptic maintenance and function.