Reduced cellular Ca(2+) availability enhances TDP-43 cleavage by apoptotic caspases

Area of Science:

• Neurobiology
• Molecular Biology
• Cellular Biology

Background:

• Accumulation of transactive response DNA binding protein (TDP-43) fragments in motor neurons is a hallmark of neurodegenerative diseases.
• TDP-43 fragments result from caspase-3 and -7 activity, which are activated by altered intracellular calcium (Ca2+) levels.
• The effect of restricted intracellular Ca2+ on TDP-43 cleavage by caspases is not well-described.

Purpose of the Study:

• To investigate the impact of restricted intracellular Ca2+ availability on TDP-43 cleavage by caspases.
• To identify novel TDP-43 fragments generated through caspase-mediated pathways.
• To compare TDP-43 cleavage products in murine and human cell lines.

Main Methods:

• Utilized various cell lineages with restricted Ca2+ availability.
• Analyzed TDP-43 cleavage by caspases-3, -7, -6, and -8.
• Identified and characterized TDP-43 fragments using biochemical methods.

Main Results:

• Restricted Ca2+ availability leads to sequential cleavage of TDP-43 by caspases-3, -7, -6, and -8.
• A novel 15kDa TDP-43 fragment was identified, alongside known 35kDa and 25kDa fragments.
• The 15kDa fragment is a major product in murine cells, while it is minor in human cells.

Conclusions:

• Caspase-mediated cleavage of TDP-43 is influenced by intracellular Ca2+ levels.
• The differential generation of TDP-43 fragments in murine versus human cells has implications for neurodegenerative disease modeling.
• Further research is needed to understand the role of the novel 15kDa TDP-43 fragment in TDP-43 proteinopathies.