Age-associated increases of α-synuclein in monkeys and humans are associated with nigrostriatal dopamine depletion: Is this the target for Parkinson's disease?

Chu, Yaping; Kordower, Jeffrey H.

doi:10.1016/j.nbd.2006.08.021

Cited by 378 publications

(355 citation statements)

References 74 publications

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“…␣-Syn is degraded in part by the lysosomal pathway, under the regulation of the cochaperone CHIP (29), and mutant forms of ␣-syn can block chaperone-mediated autophagy (30). Therefore, lysosomal failure has been proposed as a mechanism underlying the age dependence of PD (31). PARK9, a hereditary form of parkinsonism with dementia, has been recently linked to mutation of a lysosomal ATPase (19).…”

Section: Discussionmentioning

confidence: 99%

Hypothesis-based RNAi screening identifies neuroprotective genes in a Parkinson's disease model

Hamamichi

Rivas

Knight

et al. 2008

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

277

284

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Genomic multiplication of the locus-encoding human ␣-synuclein (␣-syn), a polypeptide with a propensity toward intracellular misfolding, results in Parkinson's disease (PD). Here we report the results from systematic screening of nearly 900 candidate genetic targets, prioritized by bioinformatic associations to existing PD genes and pathways, via RNAi knockdown. Depletion of 20 gene products reproducibly enhanced misfolding of ␣-syn over the course of aging in the nematode Caenorhabditis elegans. Subsequent functional analysis of seven positive targets revealed five previously unreported gene products that significantly protect against age-and dose-dependent ␣-syn-induced degeneration in the dopamine neurons of transgenic worms. These include two trafficking proteins, a conserved cellular scaffold-type protein that modulates G protein signaling, a protein of unknown function, and one gene reported to cause neurodegeneration in knockout mice. These data represent putative genetic susceptibility loci and potential therapeutic targets for PD, a movement disorder affecting Ϸ2% of the population over 65 years of age.Caenorhabditis elegans ͉ neuroprotection ͉ synuclein

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Section: Discussionmentioning

confidence: 99%

Hypothesis-based RNAi screening identifies neuroprotective genes in a Parkinson's disease model

Hamamichi

Rivas

Knight

et al. 2008

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

277

284

View full text Add to dashboard Cite

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“…Neurodegenerative diseases such as AD [97], Parkinson's [98] and Huntington's [99] disease, are each associated with the accumulation of specific protein aggregates, which play a key role in the pathogenesis of the disease. Thus, the intensity and efficacy of clearance of the damaged molecules largely determines the progression of neurodegenerative disorders [100][101][102] but also the pace of brain ageing in healthy individuals [46,103,104].…”

Section: Processes Contributing To Brain Ageingmentioning

confidence: 99%

The endocannabinoid system in normal and pathological brain ageing

Bilkei-Gorzó

2012

Phil. Trans. R. Soc. B

120

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The role of endocannabinoids as inhibitory retrograde transmitters is now widely known and intensively studied. However, endocannabinoids also influence neuronal activity by exerting neuroprotective effects and regulating glial responses. This review centres around this less-studied area, focusing on the cellular and molecular mechanisms underlying the protective effect of the cannabinoid system in brain ageing. The progression of ageing is largely determined by the balance between detrimental, proageing, largely stochastic processes, and the activity of the homeostatic defence system. Experimental evidence suggests that the cannabinoid system is part of the latter system. Cannabinoids as regulators of mitochondrial activity, as anti-oxidants and as modulators of clearance processes protect neurons on the molecular level. On the cellular level, the cannabinoid system regulates the expression of brainderived neurotrophic factor and neurogenesis. Neuroinflammatory processes contributing to the progression of normal brain ageing and to the pathogenesis of neurodegenerative diseases are suppressed by cannabinoids, suggesting that they may also influence the ageing process on the system level. In good agreement with the hypothesized beneficial role of cannabinoid system activity against brain ageing, it was shown that animals lacking CB1 receptors show early onset of learning deficits associated with age-related histological and molecular changes. In preclinical models of neurodegenerative disorders, cannabinoids show beneficial effects, but the clinical evidence regarding their efficacy as therapeutic tools is either inconclusive or still missing.

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“…Kordower et al [20,21] have reported that α-synuclein-expressing neurons in long-term surviving grafts have a reduced expression of the DA transporter (DAT), and the same group has previously reported that α-synuclein-expressing neurons in the substantia nigra in PD patients have a reduced expression of tyrosine hydroxylase [47]. These observations may be taken to suggest that the α-synuclein pathology seen in DA neurons in long-term grafts is associated with dysfunction at the synaptic level.…”

Section: Can Neural Grafts Survive and Provide Long-term Function?mentioning

confidence: 99%

Cell Therapeutics in Parkinson's Disease

Lindvall

Björklund

2011

Neurotherapeutics

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The main pathology underlying motor symptoms in Parkinson's disease (PD) is a rather selective degeneration of nigrostriatal dopamine (DA) neurons. Intrastriatal transplantation of immature DA neurons, which replace those neurons that have died, leads to functional restoration in animal models of PD. Here we describe how far the clinical translation of the DA neuron replacement strategy has advanced. We briefly summarize the lessons learned from the early clinical trials with grafts of human fetal mesencephalic tissue, and discuss recent findings suggesting susceptibility of these grafts to the disease process longterm after implantation. Mechanisms underlying graftinduced dyskinesias, which constitute the only significant adverse event observed after neural transplantation, and how they should be prevented and treated are described. We summarize the attempts to generate DA neurons from stem cells of various sources and patient-specific DA neurons from fully differentiated somatic cells, with particular emphasis on the requirements of these cells to be useful in the clinical setting. The rationale for the new clinical trial with transplantation of fetal mesencephalic tissue is described. Finally, we discuss the scientific and clinical advancements that will be necessary to develop a competitive cell therapy for PD patients.

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Age-associated increases of α-synuclein in monkeys and humans are associated with nigrostriatal dopamine depletion: Is this the target for Parkinson's disease?

Cited by 378 publications

References 74 publications

Hypothesis-based RNAi screening identifies neuroprotective genes in a Parkinson's disease model

Hypothesis-based RNAi screening identifies neuroprotective genes in a Parkinson's disease model

The endocannabinoid system in normal and pathological brain ageing

Cell Therapeutics in Parkinson's Disease

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