Loss of locus coeruleus neurons and reduced startle in parkin null mice

doi:10.1073/pnas.0401297101

Loss of locus coeruleus neurons and reduced startle in parkin null mice

^*Institute for Cell Engineering, and Departments of ^†Neurology, ^§Neuroscience, and ^¶Physiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287

Edited by Solomon H. Snyder, The Johns Hopkins University School of Medicine, Baltimore, MD (received for review February 24, 2004)

Abstract

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.

Footnotes

↵ ∥ To whom correspondence should be addressed at: Institute for Cell Engineering, Department of Neurology, The Johns Hopkins University School of Medicine, 733 North Broadway Street, Suite 731, Baltimore, MD 21205. E-mail: tdawson{at}jhmi.edu.
↵ ‡ Present address: National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore 3084433.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: ARJP, autosomal recessive juvenile parkinsonism; DOPAC, 3,4-dihydroxyphenylacetic acid; HVA, homovanillic acid; IR, immunoreactivity; KO, knockout; LC, locus coeruleus; NE, norepinephrine; PD, Parkinson's disease; SNpc, substantia nigra pars compacta; TH, tyrosine hydroxylase.