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TAR DNA binding protein of 43 kDa (TDP-43) is a nuclear factor functioning in RNA processing. It is also a major deposited protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin (FTLD-U). To understand the mechanism underlying the inclusion body formation and possible functional alteration, we studied some TDP-43 fragments and their effects on RNA processing in cell models. The results show that the 35-kDa fragment of TDP-43 (namely TDP-35, residues 90-414), but not TDP-25A (184-414), is capable of forming cytoplasmic inclusion bodies and altering pre-mRNA splicing. The inclusions formed by TDP-35 can also recruit full-length TDP-43 to cytoplasmic deposition from functionally nuclear localization. The in vitro studies demonstrate that TDP-35, rather than TDP-43 and TDP-25A, is prone to aggregation, and it further serves as a seed to facilitate aggregation of full-length TDP-43. This suggests that fragmentation of TDP-43 leads to cellular redistribution, inclusion body formation, and altered RNA processing, which are implicated in the molecular pathogenesis of ALS and FTLD. [ABSTRACT FROM AUTHOR]

α-Synuclein (α-Syn) is the major component of Lewy bodies (LBs) deposited in the brains of patients with Parkinson's disease. Synphilin-1 (Sph1) is a novel α-Syn-interacting protein also present in the LBs. However, the roles of α-Syn-Sph1 interaction in LB formation and in the related pathogenesis are still unclear. We have studied the interaction between α-Syn and Sph1 by biochemical and structural approaches and found that the central coiled-coil domain of Sphl specifically interacts with the N-terminal stretch of α-Syn. When overexpressed in HEK 293T cells, Sph1 forms inclusions together with α-Syn, but the Sph1-positive inclusions cannot recruit the N-terminally truncated α-Syn. The central portion of Sph1 can also recruit α-Syn and induce inclusion formation through its coiled-coil domain. These observations demonstrate that the α-Syn-Sph1 interaction significantly promotes the formation of cytoplasmic α-Syn inclusions, which may have implications for LB formation in neural cells. We have also elucidated solution structure of the coiled-coil domain of Sphl and its interaction with the N-terminal peptide of α-Syn. The specific interaction between α-Syn and Sphl provides mechanistic insights into the inclusion-body formation in cells and pathological implication in Parkinson's disease. [ABSTRACT FROM AUTHOR]