Protein aggregation comprises an important pathological landmark in Parkinson's disease [PD], Alzheimer's disease [AD] and the tauopathies with Parkinsonism. Parkin is an E3 ubiquitin-ligase involved in the proteasomal degradation of misfolded proteins. Loss of parkin's E3 ubiquitin-ligase function is associated with early onset Parkinsonism. Accumulation of amyloid proteins, including a-synuclein in PD and ?-amyloid in AD, is the initiating step in their respective disease progression. Several proteins, including a-synuclein, are known to be targets of parkin ubiquitin-ligase activity. Preliminary data show for the first time that wild type parkin decreases the steady-state levels of intracellular A?42, raising the possibility that intracellular ?-amyloid is also a target for the ubiquitin-ligase activity of parkin. Both A? and a-synuclein deposits variably co-exist with tau in certain overlapping neurodegenerative diseases with dementia and Parkinsonism, however, it is not known how either of them interacts with tau to provoke neurofibrillary tangle formation across the tauopathies. Preliminary data show that wild type parkin attenuates tau combined with either a-synuclein or ?-amyloid toxicity in human neurblastoma SH-SY5Y cells, but fails to significantly decrease tau toxicity alone. Therefore, parkin may reduce intracellular a-synuclein and ?-amyloid levels, thus preventing them from forming "amyloid templates" that trigger tau modification in cell culture and animal models in vivo. Parkin rescues cells from intracellular A?42 and a-synuclein toxicity as well as mitochondrial toxins-induced stress, and these effects are concurrent with decreased amyloid levels and increased proteasome activity. This research is expected to show that parkin is capable of restoring amyloid-induced mitochondrial ATP energy deficits, which affect proteasome activity to prevent toxic accumulation of proteins. I will generate gene transfer animal models to investigate the role of parkin to decrease the level of amyloid 'templates', counteracting their toxic effects on the mitochondria and alteration of tau metabolism in the spectrum of syndromes with tau cytopathy and Parkinsonism. These studies may provide a potential double-pronged therapeutic strategy involving parkin as an E3 ubiquitin-ligase to reduce intracellular protein accumulation, and mitochondrial protectant capable of restoring ATP energy levels, in the spectrum of neurodegenerative diseases with dementia and Parkinsonism.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01AG030378-05
Application #
8236961
Study Section
National Institute on Aging Initial Review Group (NIA)
Program Officer
Chen, Wen G
Project Start
2008-04-01
Project End
2013-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
5
Fiscal Year
2012
Total Cost
$127,094
Indirect Cost
$9,414
Name
Georgetown University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Hebron, Michaeline L; Algarzae, Norah K; Lonskaya, Irina et al. (2014) Fractalkine signaling and Tau hyper-phosphorylation are associated with autophagic alterations in lentiviral Tau and A*1-42 gene transfer models. Exp Neurol 251:127-38
Hebron, Michaeline; Chen, Wenqiang; Miessau, Matthew J et al. (2014) Parkin reverses TDP-43-induced cell death and failure of amino acid homeostasis. J Neurochem 129:350-61
Lonskaya, Irina; Hebron, Michaeline L; Desforges, Nicole M et al. (2014) Nilotinib-induced autophagic changes increase endogenous parkin level and ubiquitination, leading to amyloid clearance. J Mol Med (Berl) 92:373-86
Dumanis, Sonya B; DiBattista, Amanda M; Miessau, Matthew et al. (2013) APOE genotype affects the pre-synaptic compartment of glutamatergic nerve terminals. J Neurochem 124:4-14
Hebron, Michaeline L; Lonskaya, Irina; Sharpe, Kaydee et al. (2013) Parkin ubiquitinates Tar-DNA binding protein-43 (TDP-43) and promotes its cytosolic accumulation via interaction with histone deacetylase 6 (HDAC6). J Biol Chem 288:4103-15
Herman, Alexander M; Khandelwal, Preeti J; Rebeck, G William et al. (2012) Wild type TDP-43 induces neuro-inflammation and alters APP metabolism in lentiviral gene transfer models. Exp Neurol 235:297-305
Khandelwal, Preeti J; Dumanis, Sonya B; Herman, Alexander M et al. (2012) Wild type and P301L mutant Tau promote neuro-inflammation and *-Synuclein accumulation in lentiviral gene delivery models. Mol Cell Neurosci 49:44-53
Boncompagni, Simona; Moussa, Charbel E-H; Levy, Ezra et al. (2012) Mitochondrial dysfunction in skeletal muscle of amyloid precursor protein-overexpressing mice. J Biol Chem 287:20534-44
Khandelwal, Preeti J; Herman, Alexander M; Moussa, Charbel E-H (2011) Inflammation in the early stages of neurodegenerative pathology. J Neuroimmunol 238:1-11
Khandelwal, Preeti J; Herman, Alexander M; Hoe, Hyang-Sook et al. (2011) Parkin mediates beclin-dependent autophagic clearance of defective mitochondria and ubiquitinated Abeta in AD models. Hum Mol Genet 20:2091-102

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