Emerging evidence indicate considerable overlap in the pathological features of tauopathies and synucleopathies. Hyperphosphorylated tau, a toxic precursor of neurofibrillary tangles of Alzheimer's disease [PD] and other taupathies, is also found in certain synucleopathies, while conversely, a-synuclein [a-Syn], a presynaptic protein linked to Parkinson's disease, is found not only in synucleopathies but also in taupathies. We have shown that the parkinsonism-inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine [MPTP], induces hyperphosphorylation of Tau [p-Tau], with phosphorylation at multiple sites, in the presence of a-Syn, a protein linked to PD. The requirement for a-Syn in p-tau formation by MPTP was mandatory, since in a-Syn null mice and in transfected cells not expressing a-Syn, MPTP failed to induce p-Tau. Our data also shows that p-GSK-Sp, a protein linked to AD and hyperphasphorylation is activated by MPTP. Importantly, we have data in human post mortem tissue from striata of PD and PD+dementia patients, which mirror changes in protein levels we have observed in the MPTP in vitro and in vivo models. These combined data suggest a convergent pathomechanism for taupathies and synucleopathies. In this grant, we will examine the mechanisms by which MPTP and a-Syn induce p-Tau formation in the MPTP mouse model of parkinsonism, using A53T transgenic mice and a-syn overexpressor mice, and human post mortem tissues. We will determine whether aggregates of a-Syn and its A30P/A53T mutant alter protein degradative pathways and have different kinectics of p-Tau formation. We will assess the underlying mechanisms of various kinases known to hyperphosphorylate Tau, including protein kinase A, p- ERK and p-GSK-3(3. In particular, using specific inhibitors of kinases, we will reverse the MPTP-mediated degeneration in mice, as a novel method to treat synucleopathies. Since the A53T of a-synuclein has a greater propensity to aggregate compared to wild-type a-Syn, we will elucidate the mechanisms of activation of p-Tau formation in the transgenic mouse overexpressing the human form of the mutant. Parallel studies will be conducted in human post mortem tissues of PD and PD with dementia patients, to measure the clinical relevance of our findings. From such studies, it will be possible to understand the overlapping pathology and mechanisms of tauopathies and synucleopathies, and to develop common targeted therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
3R01AG028108-05S1
Application #
8522657
Study Section
Clinical Neuroscience and Disease Study Section (CND)
Program Officer
Miller, Marilyn
Project Start
2007-03-01
Project End
2013-06-30
Budget Start
2012-08-15
Budget End
2013-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$90,000
Indirect Cost
$31,935
Name
Georgetown University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Credle, Joel J; Forcelli, Patrick A; Delannoy, Michael et al. (2015) ?-Synuclein-mediated inhibition of ATF6 processing into COPII vesicles disrupts UPR signaling in Parkinson's disease. Neurobiol Dis 76:112-25
Oaks, Adam W; Marsh-Armstrong, Nicholas; Jones, Jessica M et al. (2013) Synucleins antagonize endoplasmic reticulum function to modulate dopamine transporter trafficking. PLoS One 8:e70872
Oaks, Adam W; Frankfurt, Maya; Finkelstein, David I et al. (2013) Age-dependent effects of A53T alpha-synuclein on behavior and dopaminergic function. PLoS One 8:e60378
Haggerty, Thomas; Credle, Joel; Rodriguez, Olga et al. (2011) Hyperphosphorylated Tau in an ?-synuclein-overexpressing transgenic model of Parkinson's disease. Eur J Neurosci 33:1598-610
Oaks, Adam W; Sidhu, Anita (2011) Synuclein modulation of monoamine transporters. FEBS Lett 585:1001-6
Wills, Jonathan; Credle, Joel; Haggerty, Thomas et al. (2011) Tauopathic changes in the striatum of A53T ?-synuclein mutant mouse model of Parkinson's disease. PLoS One 6:e17953
Kaul, Tiffany; Credle, Joel; Haggerty, Thomas et al. (2011) Region-specific tauopathy and synucleinopathy in brain of the alpha-synuclein overexpressing mouse model of Parkinson's disease. BMC Neurosci 12:79
Graham, Dianca R; Sidhu, Anita (2010) Mice expressing the A53T mutant form of human alpha-synuclein exhibit hyperactivity and reduced anxiety-like behavior. J Neurosci Res 88:1777-83
Wills, Jonathan; Jones, Jessica; Haggerty, Thomas et al. (2010) Elevated tauopathy and alpha-synuclein pathology in postmortem Parkinson's disease brains with and without dementia. Exp Neurol 225:210-8
Moussa, Charbel E-H (2009) Parkin attenuates wild-type tau modification in the presence of beta-amyloid and alpha-synuclein. J Mol Neurosci 37:25-36

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