Tau gene transfer, but not alpha-synuclein, induces both progressive dopamine neuron degeneration and rotational behavior in the rat.
Using a viral vector for mutant (P301L) tau, we studied the effects of gene transfer to the rat substantia nigra in terms of structural and functional properties of dopaminergic neurons. The mutant tau vector caused progressive loss of pars compacta dopaminergic neurons over time, reduced striatal dopamine content, and amphetamine-stimulated rotational behavior consistent with a specific lesion effect. In addition, structural studies demonstrated neurofibrillary tangles and neuritic pathology. Wild-type tau had similar effects on neuronal loss and rotational behavior. In contrast, mutant alpha-synuclein vectors did not induce rotational behavior, although alpha-synuclein filaments formed in nigrostriatal axons. Dopamine neuron function is affected by tau gene transfer and appears to be more susceptible to tau- rather than alpha-synuclein-related damage in this model. Both tau and alpha-synuclein are important for substantia nigra neurodegeneration models in rats, further indicating their potential as therapeutic targets for human diseases involving loss of dopamine neurons.
Klein
Ronald L
RL
Department of Pharmacology and Therapeutics, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA. klein@lsuhsc.edu
Dayton
Robert D
RD
Lin
Wen-Lang
WL
Dickson
Dennis W
DW
D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics; D008297:Male; D009043:Motor Activity / Q000235:genetics; D009069:Movement Disorders / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D016874:Neurofibrillary Tangles / Q000235:genetics / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012399:Rotation; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D024801:Tauopathies / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D051844:alpha-Synuclein / Q000235:genetics*; D016875:tau Proteins / Q000235:genetics*
D051844:alpha-Synuclein; D016875:tau Proteins; D004298:Dopamine