The cardinal pathological feature of multiple system atrophy (MSA) is the glial cytoplasmic inclusion (GCI), which is found in oligodendrocytes. A major component of the GCI is alpha-synuclein. In a series of studies, which will be carried out in transgenic (tg) mouse lines overexpressing alpha-synuclein, we will examine factors that appear to contribute to the accumulation and aggregation of alpha-synuclein.
Specific Aim 1. We hypothesize those tg mice overexpressing h[alpha]-synuclein under the control of certain neural promoters will accumulate h[alpha]-synuclein in oligodendrocytes and/or neurons and may result in formation of GCI-like alterations. We have established a tg mouse line, in which h[alpha]-synuclein is overexpressed under the control of the platelet-derived growth factor B (PDGF-B) promoter, and these tg mice demonstrate motoric deficits and accumulation of h[alpha]-synuclein in oligodendrocytes and neurons. We have established a tg mouse line in which alpha-synuclein is targeted to be overexpressed in only oligodendrocytes by placing the h[alpha]-synuclein transgene under the control of the myelin basic protein (MBP) promoter. Both strains of tg mice will undergo detailed behavioral, neurochemical and neuropathological analyses.
Specific Aim 2. We hypothesize that oxidative stress favors the accumulation of h[alpha]-synuclein. To study the effects of these factors, both strains of tg h[alpha]-synuclein mice will be crossed with superoxide dismutase (SOD) 1, SOD 2 and glutathione peroxidase knockout mice. The animals will undergo analyses as in Specific Aim 1.
Specific Aim 3. We hypothesize that nitration favors the accumulation of h[alpha]-synuclein. To study the effects of these factors, both strains of tg h[alpha]-synuclein mice will be crossed with neuronal nitric oxide synthase (nNOS) and inducible NOS (iNOS) knockout mice. The animals will undergo analyses as in Specific Aim 1.
| Wenning, Gregor; Trojanowski, John Q; Kaufmann, Horacio et al. (2018) Is multiple system atrophy an infectious disease? Ann Neurol 83:10-12 |
| Cutsforth-Gregory, Jeremy K; McKeon, Andrew; Coon, Elizabeth A et al. (2018) Ganglionic Antibody Level as a Predictor of Severity of Autonomic Failure. Mayo Clin Proc 93:1440-1447 |
| Rockenstein, Edward; Ostroff, Gary; Dikengil, Fusun et al. (2018) Combined Active Humoral and Cellular Immunization Approaches for the Treatment of Synucleinopathies. J Neurosci 38:1000-1014 |
| Coon, Elizabeth A; Ahlskog, J Eric; Silber, Michael H et al. (2018) Do selective serotonin reuptake inhibitors improve survival in multiple system atrophy? Parkinsonism Relat Disord 48:51-53 |
| Ogaki, Kotaro; Martens, Yuka A; Heckman, Michael G et al. (2018) Multiple system atrophy and apolipoprotein E. Mov Disord 33:647-650 |
| Singer, Wolfgang; Berini, Sarah E; Sandroni, Paola et al. (2017) Pure autonomic failure: Predictors of conversion to clinical CNS involvement. Neurology 88:1129-1136 |
| 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 |
| Coon, Elizabeth A; Fealey, Robert D; Sletten, David M et al. (2017) Anhidrosis in multiple system atrophy involves pre- and postganglionic sudomotor dysfunction. Mov Disord 32:397-404 |
| El-Agnaf, Omar; Overk, Cassia; Rockenstein, Edward et al. (2017) Differential effects of immunotherapy with antibodies targeting ?-synuclein oligomers and fibrils in a transgenic model of synucleinopathy. Neurobiol Dis 104:85-96 |
Showing the most recent 10 out of 159 publications
