Alpha-Synuclein Kinase

Abstract

The invention provides agents and methods for treatment of diseases associated with Lewy body diseases (LBDs) in the brain of a patient. Preferred agents include inhibitors of PLK2 kinase.

Description

RELATED APPLICATIONS[0001]This application claims priority as a continuation-in-part of U.S. patent application Ser. No. 11 / 669,093, filed Jan. 30, 2007, which claims benefit of U.S. provisional application No. 60 / 764,000, filed Jan. 31, 2006, each of which is herein incorporated by reference in its entirety for all purposes.BACKGROUND OF THE INVENTION[0002]Lewy body diseases (LBDs) are characterized by degeneration of the dopaminergic system, motor alterations, cognitive impairment, and formation of Lewy bodies (LBs). (McKeith et al, Clinical and pathological diagnosis of dementia with Lewy bodies (DLB): Report of the CDLB International Workshop, Neurology (1996) 47:1113-24). LBDs include Parkinson's disease, Diffuse Lewy body disease (DLBD), Lewy body variant of Alzheimer's disease (LBV), combined Parkinson's disease (PD) and Alzheimer's disease (AD), and the syndromes identified as multiple system atrophy (MSA). Dementia with Lewy bodies (DLB) is a term coined to reconcile differ...

AI Technical Summary

Benefits of technology

[0008]In related aspects, the invention provides a method for inhibiting phosphorylation of alpha-synuclein in a mammalian cell by reducing polo-like kinase 2 (PLK2) activity in the cell such that phosphorylation of synuclein is reduced. In a related aspect, the invention provides a method for inhibiting phosphorylation of alpha-synuclein in a mammalian cell (e.g., a neuronal cell) by contacting the cell with a compound that reduces PLK2 activity in the cell such that phosphorylation of alpha-synuclein is reduced. For example, the agent may reduce expression of a PLK2 gene product.

[0011]The invention provides a method of identifying an agent reduces alpha-synuclein phosphorylation in a mammalian cell expressing alpha-synuclein. The method includes selecting an agent that a) reduces activity of PLK2 in a cell expressing PLK2 (and optionally expressing synuclein), and b) does not reduce activity of PLK1 in a cell expressing PLK1, or reduces activity of PLK1 at a higher EC50 than for PLK2; and / or c) does not reduce activity of PLK3 in a cell expressing PLK3, or reduces activity of PLK3 at a higher EC50 than for PLK2; and / or d) does not reduce activity of PLK4 in a cell expressing PLK4, or reduces activity of PLK4 at a higher EC50 than for PLK2. The cell can be a mammalian cell overexpressing alpha-synuclein. In one embodiment the agent a) reduces activity of PLK2 in a cell expressing PLK2; b) does not reduce activity of PLK1 in a cell expressing PLK1, or reduces activity of PLK1 at a higher EC50 than for PLK2; c) does not reduce activity of PLK3 in a cell expressing PLK3, or reduces activity of PLK3 at a higher EC50 than for PLK2; and d) does not reduce activity of PLK4 in a cell expressing PLK4, or reduces activity of PLK4 at a higher EC50 than for PLK2. In a further step, the method involves determining whether the selected agent shows activity useful in treating Lewy Body Disease in an animal model of the disease or a cellular model of the disease. Animal models include transgenic animals. Cellular models include neuronally-derived cell cultures and mammalian cells over-expressing alpha-synuclein. Activities that can be assayed include reduction of the proportion of total alpha-synuclein that is phosphorylated at serine-129 or a reduction in aggregation of alpha-synuclein in the cell.

Problems solved by technology

Although their incidence continues to increase, creating a serious public health problem, to date these disorders lack approved treatments (Tanner et al., Epidemiology of Parkinson's disease and akinetic syndromes, Curr. Opin. Neurol.

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