Molecular pathophysiology of α-Synuclein : Molecular mechanisms of neurodegenerative diseases

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After biochemical investigations of SDS-insoluble materials from Alzheimer's disease (AD) brains, two unknown peptides were identified and named as non-Aβ component of AD amyloid (NAC), and the precursor protein of NAC, NACP was identified by cDNA cloning (Ueda et al. 1993). NACP is now known as human α-Synuclein (aS). Since in both AD and Parkinson's disease (PD) brains neurodegeneration occurs in those areas where aS is highly expressed, it is possible that the amount of aS is the key factor for the degeneration. In AD we have shown an altered expression of aS in abnormal synaptic terminals and dystrophic neurites. In PD and dementia with Lewy bodies (LBs), we have shown that the main filamentous component of LBs is aS, as well as with the case of main filamentous component of neuronal and glial cytoplasmic inclusions of multiple system atrophy (MSA). To understand the pathophysiological role of aS, we have performed affinity chromatography using aS column and human brain proteins and revealed tubulin to be an aS binding protein. aS induced polymerization of purified tubulin into microtubules. This activity was as high as that of tau. Mutant forms of aS lost this potential. Now we can see a striking resemblance between aS and tau : both have the same physiological function and pathological features, making abnormal structures in diseased brains known as Synucleinopathies and Tauopathies. This paper (Alim et al. JAD 2004) was press released for public as "Breaking News" from the Web site of the American Association of the Advancement of Science (AAAS) in 2004. In aS-transfected dopaminergic MES23.5 cells, we have shown the inhibition of tyrosine hydroxylase (TH) expression, suggesting a role of aS in the regulation of the TH gene. TH is a rate-limiting enzyme for the synthesis of dopamine. Also in MES23.5 cells, we have shown that oxidative stress induces nuclear translocation of the C-terminus of endogenous aS, implying a role of aS in the nucleus.