Proteomics elucidating physiological and pathological functions of TDP-43

Area of Science:

• Molecular Biology
• Neuroscience
• Biochemistry

Background:

• Trans-activation response DNA binding protein of 43 kDa (TDP-43) is vital for numerous nuclear and cytosolic cellular processes.
• Nuclear depletion and cytosolic mislocalization/aggregation of TDP-43 characterize specific neurodegenerative diseases.
• TDP-43 interacts with diverse ribonucleoprotein complexes to execute its functions.

Purpose of the Study:

• To review characterized TDP-43 ribonucleoprotein complexes and their functional contributions.
• To explore the role of post-translational modifications in TDP-43 regulation.
• To highlight the need for advanced methodologies to study TDP-43's dynamic interactions.

Main Methods:

• MS interactome studies combined with transcriptomics to identify TDP-43 protein partners.
• Analysis of post-translational modifications impacting TDP-43.
• Review of existing literature on TDP-43 ribonucleoprotein complexes and their properties.

Main Results:

• TDP-43 associates with key cellular machinery including the spliceosome, polysomes, and RNA granules.
• Post-translational modifications influence TDP-43's nucleocytoplasmic shuttling, RNA binding, phase separation, and aggregation.
• The low-complexity domain of TDP-43 mediates dynamic, low-valency interactions.

Conclusions:

• Understanding TDP-43's dynamic properties within ribonucleoprotein complexes is essential for comprehending RNA processing.
• Further research into TDP-43 complexes and modifications may lead to novel therapeutic strategies for TDPopathies.
• Innovative proximity labeling methods are needed to study TDP-43's dynamic interactions.