Familial Parkinson?s disease: a hint to elucidate the mechanisms of nigral degeneration

Kobayashi, Hirokazu; Sasaki-Hatano, Yasuko; Sato, Kenichi; Mizuno, Yoshikuni

doi:10.1007/s00415-003-1302-y

Cited by 18 publications

(13 citation statements)

References 84 publications

(93 reference statements)

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“…This is consistent with previous studies that have found reduced mitochondrial [13][14][15] and UPS [16] activity in the Parkinsonian brain. Our findings are also in line with studies of familial PD [41][42][43] and work on animal models of PD [44][45][46], which have independently implicated both metabolic systems in PD. For the first time, it is shown here that the two systems are functionally linked in the human brain.…”

Section: Regulation Of Mitochondrial and Ubiquitin-proteasome Gene Exsupporting

confidence: 91%

Transcriptome analysis reveals link between proteasomal and mitochondrial pathways in Parkinson’s disease

et al. 2006

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There is growing evidence that dysfunction of the mitochondrial respiratory chain and failure of the cellular protein degradation machinery, specifically the ubiquitin-proteasome system, play an important role in the pathogenesis of Parkinson's disease. We now show that the corresponding pathways of these two systems are linked at the transcriptomic level in Parkinsonian substantia nigra. We examined gene expression in medial and lateral substantia nigra (SN) as well as in frontal cortex using whole genome DNA oligonucleotide microarrays. In this study, we use a hypothesis-driven approach in analysing microarray data to describe the expression of mitochondrial and ubiquitin-proteasomal system (UPS) genes in Parkinson's disease (PD). Although a number of genes showed up-regulation, we found an overall decrease in expression affecting the majority of mitochondrial and UPS sequences. The down-regulated genes include genes that encode subunits of complex I and the Parkinson's-disease-linked UCHL1. The observed changes in expression were very similar for both medial and lateral SN and also affected the PD cerebral cortex. As revealed by "gene shaving" clustering analysis, there was a very significant correlation between the transcriptomic profiles of both systems including in control brains. Therefore, the mitochondria and the proteasome form a higher-order gene regulatory network that is severely perturbed in Parkinson's disease. Our quantitative results also suggest that Parkinson's disease is a disease of more than one cell class, i.e. that it goes beyond the catecholaminergic neuron and involves glia as well.

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Section: Regulation Of Mitochondrial and Ubiquitin-proteasome Gene Exsupporting

confidence: 91%

Transcriptome analysis reveals link between proteasomal and mitochondrial pathways in Parkinson’s disease

et al. 2006

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“…There is evidence that genetic factors play a key role in the development of PD. Studies of twins have provided strong evidence for an important role of environmental factors in the aetiology of typical PD [3,4]. The development of PD involves an interaction between genes and environmental factors.…”

Section: Financial Disclosures Concerning the Research Related To Thementioning

confidence: 98%

Dementia is associated with Insulin Resistance in patients with Parkinson's Disease

Bosco

Plastino

Cristiano

et al. 2012

Journal of the Neurological Sciences

128

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“…Among these, PARK2 encodes a RING domain-containing E3 ubiquitin ligase that is widely expressed throughout the nervous system but whose cellular function is poorly understood (1,(12)(13)(14)(15)(16)(17). Among the reported substrates of parkin are several proteins implicated in synaptic transmission, including CDCrel-1 (15), glycosylated ␣-synuclein, synphilin, synaptotagmin XI (18), Eps15 (19), and protein interacting with C kinase 1 (20).…”

Section: Mutations In the Park2 Gene Cause Hereditary Parkinson Diseamentioning

confidence: 99%

Pruning and loss of excitatory synapses by the parkin ubiquitin ligase

Helton¹,

Ôtsuka²,

Lee³

et al. 2008

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

100

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Mutations in the PARK2 gene cause hereditary Parkinson disease (PD).The PARK2 gene product, termed parkin, is an E3 ubiquitin ligase that mediates the transfer of ubiquitin onto diverse substrate proteins. Despite progress in defining the molecular properties and substrates of parkin, little is known about its physiological function. Here, we show that parkin regulates the function and stability of excitatory glutamatergic synapses. Postsynaptic expression of parkin dampens excitatory synaptic transmission and causes a marked loss of excitatory synapses onto hippocampal neurons. Conversely, knockdown of endogenous parkin or expression of PD-linked parkin mutants profoundly enhances synaptic efficacy and triggers a proliferation of glutamatergic synapses. This proliferation is associated with increased vulnerability to synaptic excitotoxicity. Thus, parkin negatively regulates the number and strength of excitatory synapses. Increased excitatory drive produced by disruption of parkin may contribute to the pathophysiology of PD.excitotoxicity ͉ proteasome ͉ synapse ͉ glutamate P arkinson disease (PD) is the most common neurodegenerative movement disorder (1, 2). Although classic clinical symptoms arise as a result of the loss of dopaminergic neurons of the substantia nigra, widespread neurological abnormalities are present in animal models of PD and in human disease (3-6). Heightened responsiveness to the excitatory neurotransmitter glutamate and associated excitotoxicity has been implicated in the pathogenesis of PD (7-9). However, the molecular mechanisms linking PD risk factors to altered excitability and excitotoxic vulnerability remain unclear.Mutations responsible for rare hereditary forms of PD have been identified in several human genes (10, 11). Among these, PARK2 encodes a RING domain-containing E3 ubiquitin ligase that is widely expressed throughout the nervous system but whose cellular function is poorly understood (1,(12)(13)(14)(15)(16)(17). Among the reported substrates of parkin are several proteins implicated in synaptic transmission, including CDCrel-1 (15), glycosylated ␣-synuclein, synphilin, synaptotagmin XI (18), Eps15 (19), and protein interacting with C kinase 1 (20). Parkin associates with PDZ scaffold proteins in the postsynaptic density (PSD) (21) and protects postmitotic neurons from glutamate receptor-mediated excitotoxicity (16,22), suggesting a link between parkin and glutamatergic synapse function. Consistent with this notion, mice lacking parkin display both motor and cognitive behavioral deficits and altered excitability in the hippocampus and striatum (23, 24). We hypothesized that parkin may regulate the strength of excitatory synapses. Results Postsynaptic Parkin Dampens Excitatory Synaptic Transmission.To determine the effects of postsynaptic parkin on synaptic transmission, GFP-tagged parkin (parkin-WT) was expressed in cultured rat hippocampal neurons, and miniature excitatory postsynaptic currents (mEPSCs) and miniature inhibitory postsynaptic currents (mIPSCs) were recorded...

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Familial Parkinson?s disease: a hint to elucidate the mechanisms of nigral degeneration

Cited by 18 publications

References 84 publications

Transcriptome analysis reveals link between proteasomal and mitochondrial pathways in Parkinson’s disease

Transcriptome analysis reveals link between proteasomal and mitochondrial pathways in Parkinson’s disease

Dementia is associated with Insulin Resistance in patients with Parkinson's Disease

Pruning and loss of excitatory synapses by the parkin ubiquitin ligase

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