Intersecting pathways to neurodegeneration in Parkinson's disease: Effects of the pesticide rotenone on DJ-1, α-synuclein, and the ubiquitin–proteasome system

Betarbet, Ranjita; Canet-Avilés, Rosa M.; Sherer, Todd; Mastroberardino, Pier G.; McLendon, Chris; Kim, Jin-Ho; Lund, Serena; Na, Hye-Mee; Taylor, Georgia; Bence, Neil; Kopito, Ron R.; Seo, Byoung Boo; Yagi, Takao; Yagi, Akemi; Klinefelter, Gary R.; Cookson, Mark; Greenamyre, J. Timothy

doi:10.1016/j.nbd.2005.12.003

Cited by 305 publications

(228 citation statements)

References 77 publications

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“…Rare mutations or duplication of the SNCA gene, which encodes α-syn, cause dominantly inherited PD, and α-syn is the major component of Lewy bodies and Lewy neurites, the hallmark lesions in the brain of patients with PD [1][2][3][4][5]. Increased concentration of wild-type (WT) α-syn due to genetic or environmental insults appears to be sufficient for increasing the risk of developing PD, and in high enough levels it can cause PD [5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

A Novel “Molecular Tweezer” Inhibitor of α-Synuclein Neurotoxicity in Vitro and in Vivo

et al. 2012

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Section: Introductionmentioning

confidence: 99%

A Novel “Molecular Tweezer” Inhibitor of α-Synuclein Neurotoxicity in Vitro and in Vivo

et al. 2012

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“…AlexaFluor 680 donkey anti-mouse (1:5,000; Molecular Probes, Eugene, OR) and IRDye 800 goat anti-rabbit (1:5,000; Rockland, Gilbertsville, PA) secondary antibodies were used. Blots were dried, scanned, and quantified with an Odyssey Infrared Imaging System (LiCor Biosciences) (Betarbet, et al, 2006).…”

Section: Tyrosine Hydroxylase Immunoblottingmentioning

confidence: 99%

Loss of enteric dopaminergic neurons and associated changes in colon motility in an MPTP mouse model of Parkinson's disease

Anderson

Noorian

Taylor

et al. 2007

Experimental Neurology

201

188

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Gastrointestinal (GI) dysfunction is the most common non-motor symptom of Parkinson's disease (PD). Symptoms of GI dysmotility include early satiety and nausea from delayed gastric emptying, bloating from poor small bowel coordination, and constipation and defecatory dysfunction from impaired colonic transit. Understanding the pathophysiology and treatment of these symptoms in PD patients has been hampered by the lack of investigation into GI symptoms and pathology in PD animal models. We report that the prototypical parkinsonian neurotoxin, MPTP (1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine), is a selective dopamine neuron toxin in the enteric nervous system (ENS). When examined 10 days after treatment, there was a 40% reduction of dopamine neurons in the ENS of C57Bl/6 mice administered MPTP (60 mg/kg). There were no differences in the density of cholinergic or nitric oxide neurons. Electrophysiological recording of neural-mediated muscle contraction in isolated colon from MPTP-treated animals confirmed a relaxation defect associated with dopaminergic degeneration. Behaviorally, MPTP induced a transient increase in colon motility, but no changes in gastric emptying or small intestine transit. These results provide the first comprehensive assessment of gastrointestinal pathophysiology in an animal model of PD. They provide insight into the impact of dopaminergic dysfunction on gastrointestinal motility and a benchmark for assessment of other PD model systems.

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“…Although it has been known for some time that mildly damaged mitochondrial proteins are degraded by the proteasome, it hasn't been appreciated until recently that heavily damaged mitochondrial proteins inhibit the proteasome [66][67][68][69][70]. Thus, the very strong inhibition of many subunits of the ubiquitin-proteasome system is likely a consequence of misfolded and damaged mitochondrial proteins specified by the mtDNA deletions.…”

Section: Deletions Inhibit the Ubiquitin And Proteasome Systemmentioning

confidence: 99%

Mitochondrial DNA deletions inhibit proteasomal activity and stimulate an autophagic transcript

Alemi

Prigione

Wong

et al. 2007

Free Radical Biology and Medicine

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Deletions within the mitochondrial DNA (mtDNA) cause Kearns Sayre Syndrome (KSS) and Chronic Progressive External Opthalmoplegia (CPEO). The clinical signs of KSS include muscle weakness, heart block, pigmentary retinopathy, ataxia, deafness, short stature, and dementia. The identical deletions occur and rise exponentially as humans age, particularly in substantia nigra. Deletions at >30% concentration cause deficits in basic bioenergetic parameters, including membrane potential and ATP synthesis, but it is poorly understood how these alterations cause the pathologies observed in patients. To better understand the consequences of mtDNA deletions, we microarrayed 6 cell types containing mtDNA deletions from KSS and CPEO patients. There was a prominent inhibition of transcripts encoding ubiquitin-mediated proteasome activity, and a prominent induction of transcripts involved in the AMP kinase pathway, macroautophagy, and amino acid degradation. In mutant cells, we confirmed a decrease in proteasome biochemical activity, significantly lower concentration of several amino acids, and induction of an autophagic transcript. An interpretation consistent with the data is that mtDNA deletions increase protein damage, inhibit the ubiquitin-proteasome system, decrease amino acid salvage, and activate autophagy. This provides a novel pathophysiological mechanism for these diseases, and suggests potential therapeutic strategies.

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Intersecting pathways to neurodegeneration in Parkinson's disease: Effects of the pesticide rotenone on DJ-1, α-synuclein, and the ubiquitin–proteasome system

Cited by 305 publications

References 77 publications

A Novel “Molecular Tweezer” Inhibitor of α-Synuclein Neurotoxicity in Vitro and in Vivo

A Novel “Molecular Tweezer” Inhibitor of α-Synuclein Neurotoxicity in Vitro and in Vivo

Loss of enteric dopaminergic neurons and associated changes in colon motility in an MPTP mouse model of Parkinson's disease

Mitochondrial DNA deletions inhibit proteasomal activity and stimulate an autophagic transcript

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