The relationship between the intracellular stability of tyrosine hydroxylase and the neurodegeneration regulated by α-synuclein

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In a series of earlier experiments we examined mutated forms of human tyrosine hydroxylase type 1 (hTH1), which are more stable than wild-type hTH1, because they should be promising tools for the gene therapy of Parkinson's disease (PD). We recently reported the following observations: 1) a mutant hTH1 with a deletion of its N-terminus up to Ala^<52> was much more stable than wild-type hTH1 in mammalian cells; 2) the presence of a PEST motif (a proline, glutamate/aspartate, serine, and threonine motif), which confers rapid turnover of many short-lived regulatory proteins, was predicted for the N-terminus region. In that research, we proposed that the phenomenon that N-terminus-deleted hTH1 was more stable than wild-type hTH1 might be a straightforward result of the loss of the PEST motif (PEST-1, Met^1-Lys^<12>). Therefore, one of the main aims of this study was to clarify whether the PEST-1 motif was involved in determining the degradation rate of the hTH1 protein.In this research, we clarified that 14-3-3η protein is a poisible regulator of the quantity of hTH1 protein in neuronal cells and that the N-terminus of the enzyme up to Asp^<22> is an important sequence in order for 14-3-3η protein to play such a role. However, the precise mechanism by which the 14-3-34 protein exerts its effect on the hTH1 molecule still remains to be solved. It is noteworthy that α-synuclein, which is another ubiquitous cytoplasmic chaperone and one of the main components of Lewy bodies, shares physical and functional homology with 14-3-3 proteins (sharing over 40% homology). In addition, α-synuclein binds to 14-3-3 proteins. Therefore, we believe that the research to clarify the roles of ubiquitous cytoplasmic chaperones such as 14-3-3 and α-synuclein in the proteolytic system will provide a new focus to afford a better understanding of the intracellular stability of the hTH1 molecule concerning the neurodegenaration.