An Amyloidogenic Core for TDP-43 Aggregation

TAR DNA binding protein of 43 kDa (TDP-43) is a major deposited protein in Amyotrophic Lateral Sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin (FTLD-U). Recently, researchers from Shanghai Institute of Biochemistry and Cell Biology, CAS, identified an amyloidogenic core in the C-terminal region of TDP-43 and demonstrated that structural transformation of this core region initiates TDP-43 aggregation and cytoplasmic inclusion formation.

TDP-43 is comprised of an N-terminal random coil, two RNA recognition motifs (RRMs), and a C-terminal glycine rich region (GRR). Accumulating evidence suggests that the C-terminal region, especially the 35-kDa fragment (TDP-35), plays crucial roles in TDP-43 proteinopathies. JIANG Leilei, CHE Meixia and their colleagues led by Dr. HU Hongyu focused the study on the C-terminal amyloidogenic core region of TDP-43 and its effects on TDP-43 aggregation and cytoplasmic inclusion. The results showed that this amyloidogenic core formed a helix-turn-helix structure in solution.

However, the core region was prone to aggregation and transforms from α-helix to β-sheet-rich structure during aggregation. In vitro and in cell studies demonstrated that TDP-43 was prone to aggregation and formation of cytoplasmic inclusions, but mutation or deletion in the amyloidogenic core significantly weakened its aggregation ability. Interestingly, TDP-1, a C. elegans ortholog, was not aggregation prone, but conferred the ability to form inclusions when the amyloidogenic core from TDP-43 was inserted. These results suggested that the amyloidogenic core segment was the molecular determinant of TDP-43 aggregation, and structural transformation of this core region initiateed TDP-43 aggregation and cytoplasmic inclusion formation. The finding provides a potential therapeutic target for TDP-43 proteinopathies.

This study entitled “Structural Transformation of the Amyloidogenic Core Region of TDP-43 Protein Initiates Its Aggregation and Cytoplasmic Inclusion” was published on J. Biol. Chem. on July 5^th, 2013. It was supported by the Chinese Academy of Sciences, the Ministry of Science and Technology, and the National Natural Science Foundation of China.

AUTHOR CONTACT:
HU Hongyu
Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
Phone: 86-21-54921121;
E-mail: hyhu@sibcb.ac.cn