An autopsy case of autosomal-recessive juvenile parkinsonism with a homozygous exon 4 deletion in theparkin gene

Hayashi, Shigenari; Wakabayashi, Keiji; Ishikawa, Atsushi; Nagai, Hirotaka; Saito, Masaaki; Maruyama, Mieko; Takahashi, Toshiaki; Ozawa, Tetsutaro; Tsuji, Shoji; Takahashi, Hitoshi

doi:10.1002/1531-8257(200009)15:5<884::aid-mds1019>3.0.co;2-8

Cited by 202 publications

(140 citation statements)

References 25 publications

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“…There seem to be no additional pathologic abnormalities in parkin null mice. In particular, no inclusion bodies or protein aggregates were found, consistent with the absence of such pathological findings in brains of ARJP patients (13)(14)(15).…”

Section: Discussionsupporting

confidence: 84%

“…Patients with parkin mutations also have loss of LC neurons (13)(14)(15). Given the observation that, in patients with sporadic PD, neuronal loss in the LC is more pronounced than in the SNpc (3), and that LC neurons exhibit significant pathology earlier during disease than SNpc neurons (2), it is conceivable that noradrenergic neurons of the LC are the earliest neurons to degenerate in patients with parkin mutations.…”

Section: Discussionmentioning

confidence: 99%

“…Parkin belongs to a family of proteins with a conserved ubiquitin-like domain (UBL) and RING finger motifs (11). Limited neuropathologic studies of patients with parkin mutations have found loss of dopamine neurons of the SNpc, as well as LC neurons, without the presence of Lewy bodies (13)(14)(15).…”

mentioning

confidence: 99%

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

Coelln

Thomas

Savitt

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

320

250

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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. Autosomalrecessive 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 norepinephrinedependent 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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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

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

Coelln

Thomas

Savitt

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

320

250

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“…We report here that zebrafish lack endogenous ␣-synuclein, which may cast doubt on whether key aspects of PD pathogenesis can be reproduced in a zebrafish model. ␣-Synuclein pathology is not prominent in some types of PD (62,63), and it is currently unclear whether ␣-synuclein is necessary for PD pathogenesis in all cases. However, we consider the construction of transgenic zebrafish lines expressing physiological levels of human or fish ␣-synucleins an important priority.…”

Section: Discussionmentioning

confidence: 99%

Hypokinesia and Reduced Dopamine Levels in Zebrafish Lacking β- and γ1-Synucleins

Milanese

Sager

Bai

et al. 2012

Journal of Biological Chemistry

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Background: Synucleins are implicated in Parkinson disease pathogenesis, but their functions are incompletely understood. Results: Zebrafish lacking ␤-and ␥1-synucleins showed hypokinesia and decreased dopamine levels. These abnormalities were rescued by human ␣-synuclein. Conclusion: Synucleins are necessary for spontaneous movement and dopaminergic function. Significance: A key functional role for synucleins in dopamine neurons may be relevant to Parkinson disease pathogenesis.

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“…Although the first report linked parkin mutations to autosomal recessive juvenile parkinsonism (AR-JP) with atypical clinical features (5), many more cases identified subsequently were considered typical early-onset FPD with symptoms often indistinguishable from sporadic PD (9,11). Autopsies of limited numbers of patients showed selective loss of dopaminergic neurons in the SN either in the absence (12)(13)(14)(15) or in the presence (16) of Lewy bodies. The recessive inheritance mode and variety of parkin mutations indicate a loss-of-function pathogenic mechanism.…”

mentioning

confidence: 99%

Parkin-deficient Mice Exhibit Nigrostriatal Deficits but Not Loss of Dopaminergic Neurons

Goldberg

Fleming

Palacino

et al. 2003

Journal of Biological Chemistry

820

646

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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 ␣-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. Parkinson's disease (PD)1 is an age-related movement disorder characterized by bradykinesia, rigidity, resting tremor, and postural instability. The neuropathologic hallmarks of PD are the loss of dopaminergic neurons in the substantia nigra (SN) and the presence of intraneuronal cytoplasmic inclusions known as Lewy bodies. The clinical manifestations of PD are due to progressive degeneration of dopaminergic neurons in the pars compacta of the SN that give rise to the nigrostriatal pathway, causing dopamine (DA) depletion in the striatum, where it is required for normal motor function. Little is known about the mechanisms of PD pathogenesis and nigral degeneration, although DA neurons have been shown to be susceptible to oxidative stress (1), mitochondrial defects (2), and environmental toxins (3).The recent identification of genes linked to familial forms of PD (FPD) makes it possible to investigate the pathogenic mechanism by employing genetic approaches (4 -6). Over fifty recessively inherited mutations, including deletion, frameshift, nonsense, and missense mutations, have been identified in parkin in large numbers of families, making parkin the major gene responsible for early-onset FPD (7-10). Although the first report linked parkin mutations to autosomal recessive juvenile parkinsonism (AR-JP) with atypical clinical features (5), many more cases identified subsequently were considered typical early-onset FPD with symptoms often indistinguishable from sporadic PD (9, 11). Autopsies of limited numbers of patients showed selective loss of dopaminergic neurons in the SN either in the absence (12-15) or in the ...

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An autopsy case of autosomal-recessive juvenile parkinsonism with a homozygous exon 4 deletion in theparkin gene

Cited by 202 publications

References 25 publications

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

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

Hypokinesia and Reduced Dopamine Levels in Zebrafish Lacking β- and γ1-Synucleins

Parkin-deficient Mice Exhibit Nigrostriatal Deficits but Not Loss of Dopaminergic Neurons

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