Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons.
Loss-of-function mutations in parkin are the major cause of early-onset familial Parkinson's disease. To investigate the pathogenic mechanism by which loss of parkin function causes Parkinson's disease, we generated a mouse model bearing a germline disruption in parkin. Parkin-/- mice are viable and exhibit grossly normal brain morphology. Quantitative in vivo microdialysis revealed an increase in extracellular dopamine concentration in the striatum of parkin-/- mice. Intracellular recordings of medium-sized striatal spiny neurons showed that greater currents are required to induce synaptic responses, suggesting a reduction in synaptic excitability in the absence of parkin. Furthermore, parkin-/- mice exhibit deficits in behavioral paradigms sensitive to dysfunction of the nigrostriatal pathway. The number of dopaminergic neurons in the substantia nigra of parkin-/- mice, however, is normal up to the age of 24 months, in contrast to the substantial loss of nigral neurons characteristic of Parkinson's disease. Steady-state levels of CDCrel-1, synphilin-1, and alpha-synuclein, which were identified previously as substrates of the E3 ubiquitin ligase activity of parkin, are unaltered in parkin-/- brains. Together these findings provide the first evidence for a novel role of parkin in dopamine regulation and nigrostriatal function, and a non-essential role of parkin in the survival of nigral neurons in mice.
Goldberg
Matthew S
MS
Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Fleming
Sheila M
SM
Palacino
James J
JJ
Cepeda
Carlos
C
Lam
Hoa A
HA
Bhatnagar
Anushree
A
Meloni
Edward G
EG
Wu
Nanping
N
Ackerson
Larry C
LC
Klapstein
Gloria J
GJ
Gajendiran
Mahadevan
M
Roth
Bryan L
BL
Chesselet
Marie-Francoise
MF
Maidment
Nigel T
NT
Levine
Michael S
MS
Shen
Jie
J
D000483:Alleles; D000818:Animals; D001522:Behavior, Animal; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D004594:Electrophysiology; D018095:Germ-Line Mutation; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D009474:Neurons / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics; D011954:Receptors, Dopamine / Q000378:metabolism; D013378:Substantia Nigra / Q000378:metabolism; D013997:Time Factors; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000502:physiology*
D011954:Receptors, Dopamine; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D004298:Dopamine