Loss of locus coeruleus neurons and reduced startle in parkin null mice - PubMed (original) (raw)

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

Rainer Von Coelln et al. Proc Natl Acad Sci U S A. 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.

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Figures

Fig. 1.

Fig. 1.

Targeted deletion of parkin exon 7 in the mouse genome results in the absence of parkin protein. (A) Schematic representation of the targeting strategy. (B) Southern blot of genomic DNA from WT mice (+/+) and mice heterozygous (+/-) or homozygous (-/-) for the exon 7-deleted allele. _Hae_III-digested DNA was hybridized with the probe represented in A. (C) RT-PCR with nested primers flanking exon 7. cDNA from one WT and one parkin null mouse was used as a template for PCR amplification by using primer pair A or B. (D) Northern blot of poly(A) RNA. A probe spanning exons 1–5 was used for hybridization. (E) Western blot of whole-brain lysates with a parkin-specific antibody (PRK8), demonstrating reduced expression of parkin protein in heterozygous mice and its absence in parkin null mice.

Fig. 2.

Fig. 2.

Behavioral analysis: reduced acoustic startle in parkin null mice. (A) Open field test. (B) Rotarod. (C) Acoustic startle. Data are expressed as mean ± SEM. *, P < 0.05; **, P < 0.01, analyzed by two-tailed t test.

Fig. 3.

Fig. 3.

Loss of TH-IR in the LC, but not SNpc or striatum of parkin null mice. Immunohistochemical staining for TH (C–F: with Nissl counterstain) was performed on coronal brain sections from WT (A, C, and E) and parkin KO (B, D, and F) mice. (A and B) Striatum. (C and D) Midbrain with SN and ventral tegmental area. (E and F) LC. (Insets) A lower magnification of the same sections to verify that both pictures represent equivalent planes. (All bars = 200 μm.)

Fig. 4.

Fig. 4.

Stereological analysis of reduced number of TH-positive LC neurons in parkin null mice. (A) Number of TH-positive and Nissl-positive neurons in the SNpc of aged (12- and 18-month-old) WT and parkin KO mice. (B) Number of TH-positive LC neurons in young (2-month-old) and aged (12- and 18-month-old) parkin null mice and age-matched controls. Data are expressed as mean ± SEM. *, P < 0.05, analyzed by two-tailed t test.

Fig. 5.

Fig. 5.

Reduced NE levels in discrete CNS regions of parkin null mice. Concentrations of catecholamines were determined by HPLC with electrochemical detection. (A) Striatal levels of dopamine (DA) and its metabolites. (B) Concentration of NE in discrete CNS regions of WT and parkin null mice. Data are expressed as mean ± SEM. *, P < 0.05, analyzed by two-tailed t test.

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