Increased activity of the hydrogen peroxide-producing enzyme monoamine oxidase B (MAO-B) and decreased levels of the peroxide-scavenging compound glutathione (GSH) have both been postulated to contribute to the selective demise of dopaminergic neurons of the substantia nigra (SN) associated with Parkinson's disease (PD) via production of chronic oxidative stress in these cells. Oxidative stress may in turn impinge on mitochondrial function contributing to their subsequent neurodegeneration. Loss of mitochondria function in PD has been proposed to be the result of selective inhibition of mitochondrial complex I activity, however the specific cause or causes leading to its repression are unknown. We have recently demonstrated that subtle elevations in MAO-B or decreases in GSH in dopaminergic PC12 cells in vitro akin to that which occurs during brain aging or PD result in decreased mitochondriaI complex I activity. This appears to involve both direct oxidative damage to the complex itself as well as inhibition of the TCA enzyme alpha-ketoglutarate dehydrogenase (KDGH) which provides NADH as substrate to the complex. This in turn affects the capacity of the organelle to maintain function under stress conditions. As a logical extension of our published in vitro studies, we propose to analyze mitochondrial function and neurodegeneration in transgenic mouse lines created in our laboratory which possess inducibly increased levels of glial MAO-B mimicking those which occur during aging or decreases in GSH such as occurs in PD. This will allow us to assess the effects of this phenomenon on dopaminergic neurons of the SN which undergo degeneration in PD in the context of aging and stress. The ability to induce these changes in our transgenic models will allow us to examine the consequences of elevation in the adult animal bypassing any confounding developmental effects in a dosage-dependent and reversible manner. By looking throughout the lifespan, we will be able to assess the role that aging itself plays in this process. Information gleaned through these studies will allow us to test in future therapeutic strategies to minimize the effects of these alterations on mitochondrial function as it relates to PD and associated neurodegeneration.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS045615-04
Application #
7340512
Study Section
Neurodegeneration and Biology of Glia Study Section (NDBG)
Program Officer
Sutherland, Margaret L
Project Start
2004-12-01
Project End
2008-11-30
Budget Start
2007-12-01
Budget End
2008-11-30
Support Year
4
Fiscal Year
2008
Total Cost
$425,378
Indirect Cost
Name
Buck Institute for Age Research
Department
Type
DUNS #
786502351
City
Novato
State
CA
Country
United States
Zip Code
94945
Chinta, Shankar J; Ganesan, Abirami; Reis-Rodrigues, Pedro et al. (2013) Anti-inflammatory role of the isoflavone diadzein in lipopolysaccharide-stimulated microglia: implications for Parkinson's disease. Neurotox Res 23:145-53
Siddiqui, Almas; Chinta, Shankar J; Mallajosyula, Jyothi K et al. (2012) Selective binding of nuclear alpha-synuclein to the PGC1alpha promoter under conditions of oxidative stress may contribute to losses in mitochondrial function: implications for Parkinson's disease. Free Radic Biol Med 53:993-1003
Siddiqui, Almas; Hanson, Ingrid; Andersen, Julie K (2012) Mao-B elevation decreases parkin's ability to efficiently clear damaged mitochondria: protective effects of rapamycin. Free Radic Res 46:1011-8
Chinta, Shankar J; Rajagopalan, Subramanian; Ganesan, Abirami et al. (2012) A possible novel anti-inflammatory mechanism for the pharmacological prolyl hydroxylase inhibitor 3,4-dihydroxybenzoate: implications for use as a therapeutic for Parkinson's disease. Parkinsons Dis 2012:364684
Siddiqui, Almas; Mallajosyula, Jyothi K; Rane, Anand et al. (2011) Ability to delay neuropathological events associated with astrocytic MAO-B increase in a Parkinsonian mouse model: implications for early intervention on disease progression. Neurobiol Dis 43:527-32
Siddiqui, Almas; Mallajosyula, Jyothi K; Rane, Anand et al. (2010) Ability to delay neuropathological events associated with astrocytic MAO-B increase in a Parkinsonian mouse model: implications for early intervention on disease progression. Neurobiol Dis 40:444-8
Lee, Donna W; Kaur, Deepinder; Chinta, Shankar J et al. (2009) A disruption in iron-sulfur center biogenesis via inhibition of mitochondrial dithiol glutaredoxin 2 may contribute to mitochondrial and cellular iron dysregulation in mammalian glutathione-depleted dopaminergic cells: implications for Parkinson's disease Antioxid Redox Signal 11:2083-94
Vali, Shireen; Chinta, Shankar J; Peng, Jun et al. (2008) Insights into the effects of alpha-synuclein expression and proteasome inhibition on glutathione metabolism through a dynamic in silico model of Parkinson's disease: validation by cell culture data. Free Radic Biol Med 45:1290-301
Chinta, Shankar J; Andersen, Julie K (2008) Redox imbalance in Parkinson's disease. Biochim Biophys Acta 1780:1362-7
Chinta, Shankar J; Rajagopalan, Subramanian; Butterfield, D Allan et al. (2006) In vitro and in vivo neuroprotection by gamma-glutamylcysteine ethyl ester against MPTP: relevance to the role of glutathione in Parkinson's disease. Neurosci Lett 402:137-41

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