Age-related decline in striatal dopamine content and motor performance occurs in the absence of nigral cell loss in a genetic mouse model of Parkinson's disease.
Dopamine cytotoxicity is thought to contribute towards the selective loss of substantia nigra pars compacta dopamine neurons and disease progression in Parkinson's disease. However, the long-term toxicity of dopamine in vivo has not previously been established. The vesicular monoamine transporter 2 (VMAT2) sequesters monoamines into synaptic vesicles, a process that, in addition to being important in normal transmission, may also act to keep intracellular levels of monoamine neurotransmitters below potentially toxic thresholds. The homozygous VMAT2-hypomorphic mouse has an insertion in the VMAT2 gene (Slc18a2). Consequently, VMAT2-deficient mice (VD(-/-)) have an approximately 95% reduction in VMAT2 expression and an equivalent level of dopamine depletion in the striatum which results in moderate motor impairment. Here, we show that L-DOPA induces locomotor hyperactivity in VD(-/-) mice and reverses the deficit in motor coordination and balance as tested with the rotarod. We report that evidence for cytosolic accumulation of dopamine in substantia nigra neurons in these mice is two-fold: firstly, there is reduced phosphorylation of tyrosine hydroxylase at the residue associated with catechol feedback inhibition; and, secondly, there are increased rates of dopamine turnover at 6, 12 and 24 months of age. These animals exhibit a progressive decline in striatal monoamine levels and rotarod performance with increasing age. However, despite these data, there was no loss of nigral dopamine neurons as estimated by quantification of tyrosine hydroxylase-immunoreactive cells in the substantia nigra pars compacta of old VD(-/-) mice (24-month-old), implying that these age-dependent manifestations may be due to senescence alone.
Colebrooke
Rebecca E
RE
Laboratory of Molecular Neuroscience, The Babraham Institute, Cambridge, CB2 4AT, UK.
Humby
Trevor
T
Lynch
Patrick J
PJ
McGowan
Daniel P
DP
Xia
Jing
J
Emson
Piers C
PC
D000375:Aging; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology; D015153:Blotting, Western; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D007150:Immunohistochemistry; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D009048:Motor Skills / Q000187:drug effects / Q000502:physiology; D009410:Nerve Degeneration / Q000473:pathology; D010300:Parkinson Disease / Q000503:physiopathology*; D010766:Phosphorylation; D013378:Substantia Nigra / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000187:drug effects / Q000378:metabolism; D050493:Vesicular Monoamine Transport Proteins / Q000172:deficiency
D000978:Antiparkinson Agents; C493453:Slc18a2 protein, mouse; D050493:Vesicular Monoamine Transport Proteins; D007980:Levodopa; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine