Multiple system atrophy (MSA) is a progressive, degenerative neurological disorder characterized by parkinsonism, ataxia &dysautonomia. The cardinal pathological feature of MSA is the presence of glial cytoplasmic inclusions composed of alpha-synuclein (SYN) in oligodendrocytes. Recent studies suggest that abnormal SYN accumulation in neurons &glia leads to cellular dysfunction &neurodegeneration. During the previous funding period we developed in vitro &in vivo models of MSA showing that mitochondrial damage &hyperphosphorylated SYN aggregate generation may contribute to the pathogensis of MSA. However, mechanisms by which these pathways promote oligodendrogial dysfunction &neurodegeneration are unclear. In this renewal we will investigate the role of mitochondrial dysfunction in SYN phosphorylation &toxicity. Our central hypothesis is that oxidative stress due to mitochondrial dysfuntion may promote G-protein coupled receptor kinase (GRK) activation &toxic SYN phosphorylation. The main objective is to investigate neurodegeneration in MSA-like SYN transgenic (tg) models to determine if reducing SYN accumulation represents a therapeutic strategy for MSA.
Aim 1. In order to determine the role of hyperphosphorylated SYN accumulation in oligodendrocytes in the mechanisms of neurotoxicity, we will analyze SYN accumulation &neurodegeneration in myelin basic protein (MBP)-SYN tg mice expressing wild-type (wt) human SYN or a nonphosphorylatable SYN mutant (S129A). MBP-SYNwt tg mice will be crossed with GRK2- or GRKS-deficient mice &MBP-SYNwt tg mice &MBP-SYN(S129A) tg mice will receive intra-cerebral infections with lentivirus expressing GRK2 or GRK5 under a oligodendroglial specific promoter (MBP).
Aim 2. In order to determine the role of mitochondrial dysfunction &oxidative stress on GRK activation &SYN phosphorylation, MBP-SYN (wt and S129A) mice &oligodendroglial cells will be challenged with 3- nitropropionic acid.
Aim 3. In order to determine if neuronal impairments in MSA models can be ameliorated by reducing SYN aggregation or inhibiting GRKs, MBP-SYN wt tg mice will be treated with rifampicin or GRK blockers. Behavioral performance, neurodegeneration, SYN oligomerization &phosphorylation &GRK activity will be assessed.

Public Health Relevance

Our studies will shed light on the pathogenesis of MSA, highlighting key mechanisms underlying the role of mitochndrial dysfunction and oxidative stress as they relate to SYN phosphorylation, aggregation and toxicity. The studies with rifampicin and GRK blockers will help identify new strategies for the prevention and treatment of MSA.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS044233-10
Application #
8740560
Study Section
Special Emphasis Panel (ZNS1-SRB-E)
Project Start
Project End
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
10
Fiscal Year
2014
Total Cost
$304,381
Indirect Cost
$32,920
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Loavenbruck, Adam J; Singer, Wolfgang; Mauermann, Michelle L et al. (2016) Transthyretin amyloid neuropathy has earlier neural involvement but better prognosis than primary amyloid counterpart: an answer to the paradox? Ann Neurol 80:401-11
Valera, Elvira; Spencer, Brian; Masliah, Eliezer (2016) Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders. Neurotherapeutics 13:179-89
Labbé, Catherine; Heckman, Michael G; Lorenzo-Betancor, Oswaldo et al. (2016) MAPT haplotype diversity in multiple system atrophy. Parkinsonism Relat Disord 30:40-5
Spencer, Brian; Williams, Stephanie; Rockenstein, Edward et al. (2016) α-synuclein conformational antibodies fused to penetratin are effective in models of Lewy body disease. Ann Clin Transl Neurol 3:588-606
Spencer, Brian; Kim, Changyoun; Gonzalez, Tania et al. (2016) α-Synuclein interferes with the ESCRT-III complex contributing to the pathogenesis of Lewy body disease. Hum Mol Genet 25:1100-15
Valera, Elvira; Masliah, Eliezer (2016) Combination therapies: The next logical Step for the treatment of synucleinopathies? Mov Disord 31:225-34
Valera, Elvira; Masliah, Eliezer (2016) Therapeutic approaches in Parkinson's disease and related disorders. J Neurochem 139 Suppl 1:346-352
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
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
Low, Phillip A; Reich, Stephen G; Jankovic, Joseph et al. (2015) Natural history of multiple system atrophy in the USA: a prospective cohort study. Lancet Neurol 14:710-9

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