Transactive Response DNA Binding Protein 43 kDa, known as TDP-43, is a protein found throughout the body, playing a role in various cellular functions. Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative condition that primarily impacts motor neurons, which are nerve cells controlling voluntary muscle movement. In approximately 97% of ALS cases, abnormal TDP-43 is consistently found, establishing a direct link between this protein and the disease. This article explores the normal functions of TDP-43 and how its dysfunction contributes to ALS.
The Role of TDP-43 in Healthy Cells
Under normal conditions, TDP-43 primarily resides within the nucleus of cells, though it can move between the nucleus and the cytoplasm. This protein is a member of the heterogeneous nuclear ribonucleoprotein (hnRNP) family and is involved in various aspects of RNA metabolism. Its functions include regulating gene transcription, processing pre-messenger RNA (pre-mRNA) through splicing, and influencing mRNA transport and stability.
TDP-43 is involved in the formation of stress granules and ribonucleoprotein (RNP) transport granules within the cytoplasm. It binds to both RNA and DNA, and its proper localization and activity are important for maintaining neuronal function and integrity. Cells carefully regulate TDP-43 levels, as both increases and decreases can be detrimental to cell survival.
TDP-43 Dysfunction in ALS
In ALS, TDP-43 undergoes significant changes in its location and structure. The protein mislocalizes from the nucleus to the cytoplasm, where it accumulates and aggregates into insoluble clumps. These abnormal TDP-43 aggregates are a hallmark pathology observed in most ALS cases, including both sporadic and familial forms. The aggregates are hyper-phosphorylated and ubiquitinated, indicating alterations in the protein’s modification and degradation pathways.
The mislocalization and aggregation of TDP-43 lead to two distinct yet interconnected problems. First, there is a “loss of function” where TDP-43 is no longer present in sufficient quantities in the nucleus to perform its normal duties, such as RNA processing. Second, the aggregated protein itself can acquire a “gain of toxic function,” becoming harmful to the cell. These aggregates may include fragmented TDP-43, which may be more prone to aggregation and neurotoxicity. Ubiquitination is observed on these pathological TDP-43 inclusions and may be involved in their formation or clearance.
How TDP-43 Pathology Contributes to ALS
The dysfunctional and aggregated TDP-43 contributes to neurodegeneration in ALS through several mechanisms. The loss of normal TDP-43 from the nucleus disrupts RNA processing pathways, leading to aberrant gene expression and protein production. For example, the proper splicing of genes is impaired, leading to reduced or unstable protein levels that affect motor neuron axons.
The presence of toxic TDP-43 aggregates in the cytoplasm can cause cellular stress. These aggregates can impair mitochondrial function, affecting the cell’s energy production and leading to oxidative stress. Disruptions in axonal transport are also observed due to TDP-43 pathology. This can lead to the accumulation of mitochondria and other cellular components in axons, further compromising neuronal health and contributing to motor neuron degeneration and death.
Therapeutic Approaches Targeting TDP-43
Current research into therapeutic strategies for ALS focuses on addressing TDP-43 pathology. One approach involves preventing the aggregation of TDP-43, either by targeting its misfolding or by enhancing its clearance from the cytoplasm. Efforts include developing small molecules and peptides that inhibit TDP-43 aggregation or promote its degradation.
Another strategy aims to restore TDP-43’s normal function or mitigate the downstream effects of its dysfunction. This can involve enhancing the clearance of aggregates through pathways like autophagy or the ubiquitin-proteasome system. Gene therapy and antisense oligonucleotides (ASOs) are also being explored to modulate TDP-43 levels or correct aberrant splicing events caused by its dysfunction. These approaches highlight efforts to develop effective treatments for ALS by directly targeting TDP-43 pathology.