In Vitro and In Vivo Models of TDP-43 and TDP-43 as Biomarker for Neurodegenerative Diseases

Reference #:

2007-103

Inventors/Contributors

Leonard Petrucelli Ph.D., Yongjie Zhang, Yafei Xu M.D.

Description

The abnormal accumulation of TDP-43 protein has been recently identified as the major protein constituent for several neurodegenerative diseases. The protein undergoes several post-translational modifications including phosphorylation, ubiquitination and proteolytic cleavage. The pathologic accumulation of these truncated species is believed to be pathologic. Using cell culture models, we have shown that generation of pathologic TDP-43 species is induced by caspase-3 activity. The fragmentation of TDP-43 in the 25kD and 35kD proteolytic species is also extremely reminiscent of the biochemical properties of TDP-43 from diseased brain tissue. Whereas pharmacological suppression of caspase-3 is likely not an appropriate therapeutic strategy for FTLD-U and LAS, our cell culture models do provide a screening tool for the identification of compounds that specifically prevent pathological fragmentation of TDP-43 without affecting apoptosis.

Patent Status

Pending