Molecular pathophysiology update for α-synucleinopathies 2020: What are the therapeutic targets ?

Makio Takahashi

Department of Neurology, Japanese Red Cross Osaka Hospital

A neuronal plasticity-related protein, α-synuclein (αSyn), abnormally accumulates in neurons and glial cells in Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy, correctively termed as synucleinopathies.　However, the radical treatment against synucleinopathies has not yet been established.　αSyn was identified as a major constituent of Lewy bodies (LB).　The discovery of αSyn gene abnormalities (A30P, A53T, E46K, A53E, G51D, H50Q, duplication, triplication) revealed that both structural abnormalities and the higher gene expression were associated with its pathogenesis.　Therefore, the research for PD and DLB was accelerated towards an etiological target of α-synucleinopathies.　Pathologically, the Braak’s prion-like hypothesis that αSyn is propagated from the periphery to the central have been proved from the results of animal and cell culture models.　Further,early diagnosis by biopsies to detect α-Syn from intestinal mucosa, submandibular gland, skin, etc. have been made and the risk of PD have been attempted by identifying genes in the colonic bacteria.　Particularly, αSyn accumulates in the cardiac sympathetic postganglionic fiber from an early stage, which reflects MIBG myocardial scintigraphy abnormality.　In addition, it became possible to confirm the decrease in dopamine transporter scintigraphy uptake due to the loss of dopaminergic nerve terminals.　In PD brain, pathological αSyn propagates from cell to cell through exosomes, synapses, nanotube tunnels.　Moreover, αSyn oligomeric toxicity, mitochondrial oxidative stress, disruption of autophagy, and microglial activation are also involved in neurodegeneration, which implies the complexity of PD pathogenesis.　The transmission of αSyn is intricately related to induce inflammation via toll-like receptors (TLRs).　In this review, updated molecular pathology of α-synucleinopathy as a therapeutic target and the outline of current therapeutic development were discussed.

Address correspondence to Dr. Makio Takahashi, Department of Neurology, Japanese Red Cross Osaka Hospital（5-30 Fudegasakicho, Tennoji-ku, Osaka-shi, Osaka 543-8555, Japan）