Alpha-synuclein assembly as a therapeutic target of Parkinson's disease and related disorders.
Lewy bodies (LBs) and Lewy neurites (LNs) in the brain constitute the main histopathological features of Parkinson's disease (PD) and dementia with Lewy bodies (DLB), and are comprised of amyloid-like fibrils composed of a small protein ( approximately 14 kDa) named alpha-synuclein (alphaS). As the aggregation of (alphaS in the brain has been implicated as a critical step in the development of the diseases, the current search for disease-modifying drugs is focused on modification of the process of (alpha S deposition in the brain. In this article, the recent developments on the molecules that inhibit the formation of alpha-synuclein fibrils (falphaS) as well as the oligomerization of alphaS are reviewed. Recently, various compounds such as curcumin, nicotine and wine-related polyphenols have been reported to inhibit the formation of falphaS, and to destabilize preformed falphaS at pH 7.5 at 37 degrees C in vitro. Although the mechanisms by which these compounds inhibit falphaS formation from falphaS, and destabilize preformed falphaS are still unclear, they could be key molecules for the development of preventives and therapeutics for PD and other alpha-synucleinopathies.
Ono
Kenjiro
K
Department of Neurology & Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, Kanazawa 920-8640, Japan.
Hirohata
Mie
M
Yamada
Masahito
M
D000818:Animals; D000978:Antiparkinson Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000378:metabolism; D003704:Dementia / Q000188:drug therapy / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D016631:Lewy Bodies / Q000378:metabolism; D015394:Molecular Structure; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism; D013329:Structure-Activity Relationship; D051844:alpha-Synuclein / Q000378:metabolism*
D000978:Antiparkinson Agents; D051844:alpha-Synuclein