Loss of locus coeruleus neurons and reduced startle in parkin null mice.
Parkinson's disease (PD) is the most common neurodegenerative movement disorder and is characterized pathologically by degeneration of catecholaminergic neurons of the substantia nigra pars compacta and locus coeruleus, among other regions. Autosomal-recessive juvenile Parkinsonism (ARJP) is caused by mutations in the PARK2 gene coding for parkin and constitutes the most common familial form of PD. The majority of ARJP-associated parkin mutations are thought to be loss of function-mutations; however, the pathogenesis of ARJP remains poorly understood. Here, we report the generation of parkin null mice by targeted deletion of parkin exon 7. These mice show a loss of catecholaminergic neurons in the locus coeruleus and an accompanying loss of norepinephrine in discrete regions of the central nervous system. Moreover, there is a dramatic reduction of the norepinephrine-dependent startle response. The nigrostriatal dopaminergic system does not show any impairment. This mouse model will help gain a better understanding of parkin function and the mechanisms underlying parkin-associated PD.
Von Coelln
Rainer
R
Institute for Cell Engineering, and Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Thomas
Bobby
B
Savitt
Joseph M
JM
Lim
Kah Leong
KL
Sasaki
Masayuki
M
Hess
Ellen J
EJ
Dawson
Valina L
VL
Dawson
Ted M
TM
D000316:Adrenergic alpha-Agonists / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D005091:Exons; D005260:Female; D017353:Gene Deletion; D006801:Humans; D008125:Locus Coeruleus / Q000166:cytology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism; D013216:Reflex, Startle / Q000235:genetics / Q000502:physiology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
D000316:Adrenergic alpha-Agonists; D014446:Tyrosine 3-Monooxygenase; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D009638:Norepinephrine