This proposal is for molecular genetic assessment of SNCA in alpha-synucleinopathy. Our data shows alpha-synuclein overexpression is sufficient to give rise to a spectrum of Parkinsonism disorders, including Parkinson's disease, parkinsonism and dementia, dementia with Lewy bodies and multiple system atrophy; alpha-synuclein is undoubtedly a central component in sporadic and familial disease.
Our aims are to: 1) identify genetic variability in the SNCA locus and determine what contribution it has to these phenotypes; 2) molecularly, clinically and pathologically characterize SNCA multiplication mutations;, 3) quantify SNCA gene expression in normal aging and disease, and; 4) functionally assess genetic variability within the gene and its promoter. Furthermore, we are to examine the transcriptional consequence of alpha-synuclein over-expression, in model systems, in human brain tissue from cases with SNCA multiplication. Our objective is to provide meaningful molecular diagnoses to reclassify this heterogeneous group of diseases, into distinct groups, for further longitudinal and pathological assessment. As alpha-synuclein has an extended half-life (approximately 30hrs), thus our work is focused on characterizing SNCA genetic variability, transcriptional regulation and mRNA expression. We posit reduction in alpha-synuclein expression may provide a powerful therapeutic strategy to prevent alpha-synucleinopathy or halt its progression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
5P50NS040256-10
Application #
7687303
Study Section
Special Emphasis Panel (ZNS1)
Project Start
Project End
Budget Start
2008-09-01
Budget End
2009-08-31
Support Year
10
Fiscal Year
2008
Total Cost
$257,202
Indirect Cost
Name
Mayo Clinic Jacksonville
Department
Type
DUNS #
153223151
City
Jacksonville
State
FL
Country
United States
Zip Code
32224
Verma, Manish; Callio, Jason; Otero, P Anthony et al. (2017) Mitochondrial Calcium Dysregulation Contributes to Dendrite Degeneration Mediated by PD/LBD-Associated LRRK2 Mutants. J Neurosci 37:11151-11165
Sanchez-Contreras, Monica; Heckman, Michael G; Tacik, Pawel et al. (2017) Study of LRRK2 variation in tauopathy: Progressive supranuclear palsy and corticobasal degeneration. Mov Disord 32:115-123
Hassan, Anhar; Heckman, Michael G; Ahlskog, J E et al. (2016) Association of Parkinson disease age of onset with DRD2, DRD3 and GRIN2B polymorphisms. Parkinsonism Relat Disord 22:102-5
Yue, M; Hinkle, K M; Davies, P et al. (2015) Progressive dopaminergic alterations and mitochondrial abnormalities in LRRK2 G2019S knock-in mice. Neurobiol Dis 78:172-95
Cornejo-Olivas, Mario R; Torres, Luis; Mata, Ignacio F et al. (2015) A Peruvian family with a novel PARK2 mutation: Clinical and pathological characteristics. Parkinsonism Relat Disord 21:444-8
Verma, Manish; Steer, Erin K; Chu, Charleen T (2014) ERKed by LRRK2: a cell biological perspective on hereditary and sporadic Parkinson's disease. Biochim Biophys Acta 1842:1273-81
Sundal, Christina; Fujioka, Shinsuke; Van Gerpen, Jay A et al. (2013) Parkinsonian features in hereditary diffuse leukoencephalopathy with spheroids (HDLS) and CSF1R mutations. Parkinsonism Relat Disord 19:869-77
Boeve, Bradley F (2013) Idiopathic REM sleep behaviour disorder in the development of Parkinson's disease. Lancet Neurol 12:469-82
Foroutan, Parastou; Murray, Melissa E; Fujioka, Shinsuke et al. (2013) Progressive supranuclear palsy: high-field-strength MR microscopy in the human substantia nigra and globus pallidus. Radiology 266:280-8
Jiang, Peizhou; Gan, Ming; Ebrahim, Abdul Shukkur et al. (2013) Adenosine monophosphate-activated protein kinase overactivation leads to accumulation of ýý-synuclein oligomers and decrease of neurites. Neurobiol Aging 34:1504-15

Showing the most recent 10 out of 205 publications