The TAR DNA-binding protein 43, known as TDP-43, is a protein found in human cells. It helps maintain cellular health, especially in the nervous system. When TDP-43 changes its structure or location, it can lead to proteinopathy. Proteinopathy is a group of diseases where proteins abnormally fold, clump, or accumulate, interfering with cell function and becoming toxic. TDP-43 proteinopathy is a significant contributor to various neurodegenerative diseases.
Understanding TDP-43 and Proteinopathy
TDP-43 resides in the nucleus of healthy cells, performing functions related to genetic information. It processes RNA, a molecule that carries instructions from DNA for making proteins. TDP-43 regulates gene expression by influencing how RNA is spliced, transported, and stabilized. It binds to both messenger RNA (mRNA) and DNA, regulating mRNA splicing, stability, translation, and gene transcription. This protein also participates in creating microRNAs (miRNAs), small RNA molecules that control gene expression.
In TDP-43 proteinopathy, the protein misfolds and aggregates, forming clumps or inclusions primarily in the cytoplasm of neurons and glial cells in the brain and spinal cord. These aggregates are often hyper-phosphorylated and ubiquitinated, meaning they have abnormal chemical tags attached. The mislocalization of TDP-43 from the nucleus to the cytoplasm, along with its aggregation, disrupts its normal functions and leads to cellular dysfunction. TDP-43 is intrinsically prone to aggregation, and certain genetic mutations can accelerate this process.
Diseases Associated with TDP-43 Proteinopathy
TDP-43 proteinopathy is a hallmark of several neurodegenerative conditions. The two most prominent diseases linked to TDP-43 pathology are Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). In ALS, a progressive motor neuron disease, TDP-43 inclusions are found in nearly 97% of sporadic cases and most familial cases not caused by SOD1 mutations. ALS is characterized by the degeneration of motor neurons in the brain and spinal cord, leading to muscle weakness, paralysis, and respiratory failure.
Frontotemporal Dementia (FTD), which often overlaps clinically with ALS, frequently presents with TDP-43 aggregates. FTD is a group of disorders primarily affecting the frontal and temporal lobes of the brain, resulting in changes in behavior, personality, and language. While ALS and FTD are the primary associations, TDP-43 proteinopathy has also been observed in a subset of Alzheimer’s disease, Parkinson’s disease, and Limbic-predominant Age-related TDP-43 Encephalopathy (LATE). In these conditions, TDP-43 pathology is often restricted to specific brain regions, such as the mesial temporal structures.
How TDP-43 Dysfunction Drives Disease
Misfolding and aggregation of TDP-43 contribute to neuronal dysfunction and death through multiple mechanisms. One aspect is the loss of normal TDP-43 function in the nucleus. When TDP-43 moves from the nucleus to the cytoplasm and aggregates, it can no longer perform its RNA processing duties, leading to disrupted mRNA splicing, altered non-coding RNA processing, and issues with RNA granule dynamics. This nuclear depletion can result in the degradation and reduction of various RNAs, as well as altered splicing events, ultimately impacting protein production.
In addition to losing its normal function, aggregated TDP-43 gains toxic properties. These insoluble aggregates interfere with various cellular processes, burdening the cell’s protein quality-control systems. Mislocalized and aggregated TDP-43 can enhance further mislocalization of nuclear TDP-43 and hinder intracellular transport. This includes disrupting mitochondrial function, as TDP-43 aggregates can bind to mitochondrial DNA, leading to imbalances in mitochondrial activity and reduced ATP production.
Cellular stress, including oxidative stress, can promote TDP-43 mislocalization and defective splicing activity. Abnormalities in calcium signaling, often linked to impaired communication between the endoplasmic reticulum and mitochondria, can also contribute to cellular damage and activate cell death pathways. Neuroinflammation also plays a role, as TDP-43 pathology can trigger the release of mitochondrial DNA into the cytoplasm, which then activates inflammatory pathways.
Current Research and Therapeutic Approaches
Current research focuses on understanding the complex mechanisms underlying TDP-43 proteinopathy to develop effective treatments. One strategy involves preventing TDP-43 aggregation or enhancing its clearance from cells. Scientists are exploring ways to restore TDP-43’s normal function, for example, by ensuring it remains in the nucleus where it performs its RNA processing roles. This includes investigating strategies that can mitigate genetic risk, such as using antisense oligonucleotides.
Another research avenue involves targeting the downstream effects of TDP-43 pathology, such as neuroinflammation and mitochondrial dysfunction. Studies have shown that inhibiting the interaction between TDP-43 and p65, a protein involved in inflammation, can reduce neuroinflammatory changes and improve cognitive and motor deficits in mouse models. Improving mitochondrial integrity and increasing energy production are also being investigated as solutions for addressing TDP-43 pathology. Despite challenges in developing therapies for complex neurodegenerative diseases, ongoing research provides hope for future treatments that could prevent TDP-43 aggregation, enhance its removal, or restore its healthy functions.