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Structure, Formation, Synthesis and detection, Pathophysiology of TDP43

TDP43 (TAR DNA-binding protein 43) is a protein that is primarily found in the nucleus of cells and is involved in the regulation of gene expression. It has also been implicated in several neurodegenerative diseases.


TDP43 is a 414 amino acid protein that contains two RNA recognition motifs (RRMs) and a C-terminal glycine-rich domain. The glycine-rich domain can be subject to post-translational modifications, such as phosphorylation and ubiquitination, that are associated with its pathological aggregation in neurodegenerative diseases.

Formation and Synthesis: 

TDP43 is synthesized in the cytoplasm of cells and is subsequently transported to the nucleus. Its activity is tightly regulated by a range of factors, including alternative splicing, post-translational modifications, and interactions with other proteins.

In neurodegenerative diseases, the exact mechanisms by which TDP43 aggregation occurs are not fully understood, but it is believed to involve a combination of genetic, environmental, and molecular factors. In some cases, mutations in the TDP43 gene have been linked to increased aggregation and disease risk.


There are a number of methods that can be used to detect TDP43, including immunohistochemistry, western blotting, and ELISA. These techniques can be used to identify the presence of TDP43 in tissue samples or body fluids such as cerebrospinal fluid (CSF). In addition, imaging techniques such as magnetic resonance imaging (MRI) and positron emission tomography (PET) can be used to visualize TDP43 accumulation in the brain.


TDP43 pathology is associated with several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other TDP43 proteinopathies. In these diseases, TDP43 protein can mislocalize from the nucleus to the cytoplasm, where it can aggregate into pathological inclusions. This aggregation can lead to the disruption of cellular processes and neuronal dysfunction and death.

The exact mechanisms by which TDP43 pathology leads to neurodegeneration are not fully understood, but it is believed to involve a combination of cellular toxicity, immune system activation, and disruption of RNA processing and transport. The accumulation of TDP43 can lead to the sequestration of other RNA-binding proteins and the misregulation of gene expression, which can contribute to neuronal dysfunction and death.

Therapeutic strategies for TDP43 proteinopathies are currently focused on reducing the accumulation and toxicity of TDP43 protein. One approach involves the use of small molecule inhibitors that prevent the formation of TDP43 aggregates or promote their clearance. Other strategies include the use of immunotherapies that target TDP43 protein aggregates, as well as gene therapies that aim to reduce the production of TDP43 protein. In addition, symptomatic treatments such as cognitive and behavioral therapies, as well as medications to manage psychiatric symptoms, are often used in the treatment of TDP43 proteinopathies. However, there is still much to learn about the mechanisms underlying TDP43 protein aggregation and the development of effective therapies for these disorders.