Abnormal accumulation and misfolding of a-synuclein (SYN) and amyloid-p protein (A|3) may be at the root of a wide spectrum of neurodegenerative disorders leading to dementia, parkinsonism, and autonomic dysfunction. These disorders, called Lewy body diseases, account for the great majority of cases with combined dementia and movement disorders in the U.S. Previously, we showed that A(31-42 enhances the aggregation and toxicity of SYN. In the previous funding period, we focused on the involvement of the lysosomal-endosomal pathway in the copathogenic synergism between A|31-42 and SYN. Our studies showed that A|31-42 and SYN promote neurodegeneration by interfering with autophagy and reducing the clearance of other neuronal proteins, such as parkin and cytoskeletal proteins. In this proposal, we we will test the hypothesis that A(31-42 activates calcium-dependent proteases in a glutamate receptor-dependent manner, which, in turn, results in the generation of SYN fragments that promote the formation of pathogenic SYN oligomers. We further hypothesize that this pathogenic cascade is engaged most readily in limbic and striatal neurons, which are particularly vulnerable to Lewy body diseases. To test these hypotheses, we propose the following specific aims.
Aim 1 : To determine if the coexpression of APP/A|3 and SYN affects the vulnerability of specific neuronal populations in the hippocampus and striatum (in collaboration with Project 5 and Cores C, D).
Aim 2 : To determine, in cultured neurons, if the copathogenic effects of A(3 and SYN depend on glutamate receptors and SYN cleavage (with Projects 1-3 and Cores B and D).
Aim 3 : To determine by genetic ablation whether the copathogenic effects of A[3 and SYN depend on the activation of a specific glutamate receptor in vivo (with Project 1).
Aim 4 : To determine if the impairments of transgenic mice expressing SYN and A(3 can be prevented or ameliorated by inhibiting glutamate receptors or promoting A(3 clearance (with Project 5 and Cores C and D). In collaboration with other components of the program, this project will help elucidate mechanisms of selective vulnerability and determine if interventions aimed at A|3 or A|3-dependent pathways might be useful in preventing or treating Lewy body diseases.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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J. David Gladstone Institutes
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Valera, Elvira; Spencer, Brian; Mott, Jennifer et al. (2017) MicroRNA-101 Modulates Autophagy and Oligodendroglial Alpha-Synuclein Accumulation in Multiple System Atrophy. Front Mol Neurosci 10:329
Valera, Elvira; Spencer, Brian; Fields, Jerel A et al. (2017) Combination of alpha-synuclein immunotherapy with anti-inflammatory treatment in a transgenic mouse model of multiple system atrophy. Acta Neuropathol Commun 5:2
Spencer, Brian; Desplats, Paula A; Overk, Cassia R et al. (2016) Reducing Endogenous ?-Synuclein Mitigates the Degeneration of Selective Neuronal Populations in an Alzheimer's Disease Transgenic Mouse Model. J Neurosci 36:7971-84
Spencer, Brian; Kim, Changyoun; Gonzalez, Tania et al. (2016) ?-Synuclein interferes with the ESCRT-III complex contributing to the pathogenesis of Lewy body disease. Hum Mol Genet 25:1100-15
Valera, E; Monzio Compagnoni, G; Masliah, E (2016) Review: Novel treatment strategies targeting alpha-synuclein in multiple system atrophy as a model of synucleinopathy. Neuropathol Appl Neurobiol 42:95-106
Spencer, Brian; Potkar, Rewati; Metcalf, Jeff et al. (2016) Systemic Central Nervous System (CNS)-targeted Delivery of Neuropeptide Y (NPY) Reduces Neurodegeneration and Increases Neural Precursor Cell Proliferation in a Mouse Model of Alzheimer Disease. J Biol Chem 291:1905-20
Valera, Elvira; Masliah, Eliezer (2016) Therapeutic approaches in Parkinson's disease and related disorders. J Neurochem 139 Suppl 1:346-352
Valera, Elvira; Masliah, Eliezer (2016) Combination therapies: The next logical Step for the treatment of synucleinopathies? Mov Disord 31:225-34
Valera, Elvira; Spencer, Brian; Masliah, Eliezer (2016) Immunotherapeutic Approaches Targeting Amyloid-?, ?-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders. Neurotherapeutics 13:179-89
Mandler, Markus; Valera, Elvira; Rockenstein, Edward et al. (2015) Active immunization against alpha-synuclein ameliorates the degenerative pathology and prevents demyelination in a model of multiple system atrophy. Mol Neurodegener 10:10

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