Journal ArticleDOI
Understanding cell death in Parkinson's disease
Peter Jenner,C. W. Olanow +1 more
TLDR
Evidence enables us to hypothesize that a failure to process structurally modified proteins in regions of the brain exhibiting oxidative stress is a cause of both familial and sporadic PD.Abstract:
Current concepts of the cause of Parkinson's disease (PD) suggest a role for both genetic and environmental influences. Common to a variety of potential causes of nigral cell degeneration in PD is the involvement of oxidative stress. Postmortem analysis shows increased levels of iron, decreased complex I activity, and a decrease in reduced glutathione (GSH) levels. The decrease in GSH levels may be a particularly important component of the cascade of events leading to cell death because it occurs in the presymptomatic stage of PD and may directly induce nigral cell degeneration or render neurons susceptible to the actions of toxins. There is evidence suggesting that oxidative stress might originate in glial cells rather than in neurons, and alterations in glial function may be an important contributor to the pathologic process that occurs in PD. Oxidative damage occurs in the brain in PD, as shown by increased lipid peroxidation and DNA damage in the substantia nigra. Increased protein oxidation is also apparent, but this occurs in many areas of the brain and raises the specter of a more widespread pathologic process occurring in PD to which the substantia nigra is particularly vulnerable. The inability of the substantia nigra to handle damaged or mutant (eg, α-synuclein) proteins may lead to their aggregation and deposition and to the formation of Lewy bodies. Indeed, Lewy bodies stain for both α-synuclein and nitrated proteins. Current evidence enables us to hypothesize that a failure to process structurally modified proteins in regions of the brain exhibiting oxidative stress is a cause of both familial and sporadic PD.read more
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Journal ArticleDOI
Hereditary Early-Onset Parkinson's Disease Caused by Mutations in PINK1
Eriza Maria Valente,Patrick M. Abou-Sleiman,Viviana Caputo,Miratul M. K. Muqit,Kirsten Harvey,Suzana Gispert,Zeeshan Ali,Domenico Del Turco,Anna Rita Bentivoglio,Daniel G. Healy,Alberto Albanese,Robert L. Nussbaum,Rafael González-Maldonado,Thomas Deller,S Salvi,Pietro Cortelli,William P. Gilks,David S. Latchman,Roberk J. Harvey,Bruno Dallapiccola,Georg Auburger,Nicholas W. Wood +21 more
TL;DR: The identification of two homozygous mutations affecting the PINK1 kinase domain in three consanguineous PARK6 families provide a direct molecular link between mitochondria and the pathogenesis of PD.
Journal ArticleDOI
Creatine and Creatinine Metabolism
Markus Wyss,Rima Kaddurah-Daouk +1 more
TL;DR: A comprehensive survey of the many intriguing facets of creatine (Cr) and creatinine metabolism is presented, encompassing the pathways and regulation of Cr biosynthesis and degradation, species and tissue distribution of the enzymes and metabolites involved, and of the inherent implications for physiology and human pathology.
Journal ArticleDOI
Oxidative stress in Parkinson's disease
TL;DR: Oxidative stress contributes to the cascade leading to dopamine cell degeneration in Parkinson's disease (PD), but oxidative stress is intimately linked to other components of the degenerative process, such as mitochondrial dysfunction, excitotoxicity, nitric oxide toxicity and inflammation.
Journal ArticleDOI
Iron, brain ageing and neurodegenerative disorders
TL;DR: By studying the accumulation and cellular distribution of iron during ageing, this work should be able to increase the understanding of these neurodegenerative disorders and develop new therapeutic strategies.
Journal ArticleDOI
Molecular pathways of neurodegeneration in Parkinson's disease.
Ted M. Dawson,Valina L. Dawson +1 more
TL;DR: Strategies aimed at restoring complex I activity, reducing oxidative stress and α-synuclein aggregation, and enhancing protein degradation may hold particular promise as powerful neuroprotective agents in the treatment of PD.
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