Parkin is protective for substantia nigra dopamine neurons in a tau gene transfer neurodegeneration model.
Parkin is a ubiquitin ligase involved in the ubiquitin-proteasome system. Elevating parkin expression in cells reduces markers of oxidative stress while blocking parkin expression increases oxidative stress. In parkin gene knock down mouse and fly models, mitochondria function is deficient. Parkin is neuroprotective against a variety of toxic insults, while it remains unclear which of the above properties of parkin may mediate the protective actions. One of the models for which parkin is protective is overexpression of alpha-synuclein, a protein that self-aggregates in Parkinson disease. The microtubule-associated protein tau is another protein that self-aggregates in specific neurodegenerative diseases that also involve loss of dopamine neurons such as frontotemporal dementia with parkinsonism linked to chromosome 17, progressive supranuclear palsy and corticobasal degeneration. We recently developed a tau-induced dopaminergic degeneration model in rats using adeno-associated virus vectors. In this study, we successfully targeted either a mixed tau/parkin vector or mixed tau/control vector to the rat substantia nigra. While there was significant loss of dopamine neurons in the tau/control group relative to uninjected substantia nigra, there was no cell loss in the tau/parkin group. We found no difference in total tau levels between tau/control and tau/parkin groups. Parkin therefore protects dopamine neurons against tau as it does against alpha-synuclein, which further supports parkin as a therapeutic target for diseases involving loss of dopamine neurons.
Klein
Ronald L
RL
Department of Pharmacology, Toxicology and Neuroscience, Louisiana State University Health Sciences Center (LSUHSC), 1501 Kings Highway, Shreveport, LA 71130, USA. klein@lsuhsc.edu
Dayton
Robert D
RD
Henderson
Karen M
KM
Petrucelli
Leonard
L
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008297:Male; D009410:Nerve Degeneration / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism
D018696:Neuroprotective Agents; D016875:tau Proteins; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D004298:Dopamine