CAUSES AND CONSEQUENCES OF ALPHA-SYNUCLEIN AGGREGATION

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Parkinson's disease (PD) and related Lewy body diseases are associated with the abnormal intraneuronal accumulation of alpha-synuclein. Mutations that enhance the propensity of alpha-synuclein to aggregate cause early onset familial PD. Notably, the majority of patients with Alzheimer's disease (AD) also have alpha-synuclein immunoreactive Lewy bodies and a substantial proportion of them develop a form of parkinsonism that defies conventional therapeutic approaches. This suggests that factors involved in the pathogenesis of AD might promote the development of particularly recalcitrant forms of PD. We have shown that amyloid beta peptides (Abeta), which play a central role in AD pathogenesis, promote the intracellular accumulation of alpha-synuclein and accelerate alpha-synuclein-dependent motor deficits in alpha-synuclein/amyloid precursor protein transgenic mice, an animal model that mimics aspects of Lewy body disease. However, the mechanisms underlying these effects remain unknown. The main objectives of this proposal are to elucidate these mechanisms and to determine whether blocking Abeta effects might prevent or ameliorate PD and other Lewy body diseases. In Aim 1 we will determine whether the increase in neuronal alpha-synuclein accumulation and in alpha-synuclein-dependent deficits in a transgenic mouse model of Lewy body disease depends on the ratio of the two predominant Abeta species (Abeta1-42/Abeta1-40). For this purpose, alpha-synuclein transgenic mice will be crossed with wildtype or mutant human amyloid precursor protein (hAPP) transgenic mice and detailed biochemical, neuropathological and behavioral analysis will be performed. These experiments will be complemented with in vitro studies in alpha-synuclein-transfected cell fines treated with Abeta1-42 or Abeta1-40 or a mixture of both. In Aim 2 we will determine whether the increase in neuronal alpha-synuclein accumulation and in alpha-synuclein-dependent deficits in a transgenic mouse model of Lewy body disease depends on the uptake of secreted Abeta via the LDL receptor-related protein (LRP). For this purpose, mice expressing both alpha-synuclein and wildtype or mutant hAPP will be crossed with receptor associated protein-deficient mice, which have reduced LRP expression. These experiments will be complemented with in vitro studies in alpha-synuclein-transfected cell lines. In Aim 3 we will determine whether Abeta-dependent alpha-synuclein aggregation and alpha-synuclein-dependent neuronal deficits can be reduced by antioxidants. For this purpose, alpha-synuclein/hAPP mice will be crossed with superoxide dismutase 1 or 2 transgenic mice. These experiments will be complemented with in vitro studies in synuclein-transfected cell lines treated with antioxidants. These experiments will shed light on the overlap between AD and PD and on the role of hAPP/Abeta in the pathogenesis of PD and other Lewy body diseases.