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Free Radic Biol Med. 2013 Sep;62:132-144. doi: 10.1016/j.freeradbiomed.2013.01.018. Epub 2013 Feb 4.

Parkinson disease: from pathology to molecular disease mechanisms.

Author information

1
Parkinson's Disease Research Group, Centre for Neuroinflammation & Neurodegeneration, Division of Brain Sciences, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, London, UK.
2
Neurodegenerative Diseases Research Group, Institute of Pharmaceutical Science, School of Biomedical Sciences, King's College London, London SE1 9NH, UK. Electronic address: peter.jenner@kcl.ac.uk.

Abstract

Parkinson disease (PD) is a complex neurodegenerative disorder with both motor and nonmotor symptoms owing to a spreading process of neuronal loss in the brain. At present, only symptomatic treatment exists and nothing can be done to halt the degenerative process, as its cause remains unclear. Risk factors such as aging, genetic susceptibility, and environmental factors all play a role in the onset of the pathogenic process but how these interlink to cause neuronal loss is not known. There have been major advances in the understanding of mechanisms that contribute to nigral dopaminergic cell death, including mitochondrial dysfunction, oxidative stress, altered protein handling, and inflammation. However, it is not known if the same processes are responsible for neuronal loss in nondopaminergic brain regions. Many of the known mechanisms of cell death are mirrored in toxin-based models of PD, but neuronal loss is rapid and not progressive and limited to dopaminergic cells, and drugs that protect against toxin-induced cell death have not translated into neuroprotective therapies in humans. Gene mutations identified in rare familial forms of PD encode proteins whose functions overlap widely with the known molecular pathways in sporadic disease and these have again expanded our knowledge of the neurodegenerative process but again have so far failed to yield effective models of sporadic disease when translated into animals. We seem to be missing some key parts of the jigsaw, the trigger event starting many years earlier in the disease process, and what we are looking at now is merely part of a downstream process that is the end stage of neuronal death.

KEYWORDS:

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 1-methyl-4-phenylpyridinium; 6-OHDA; 6-hydroxy dopamine; DBS; Free radicals; GBA; GWAS; Genes; HLA; IL; Inflammation; LAMP2A; LPS; LRRK2; MAO-B; MPP(+); MPTP; Mitochondrial dysfunction; NMS; Neuroprotection; Oxidative stress; PD; PGC-1α; PINK1; Parkinson disease; Protein handling; SNc; STN; TNF-α; UCH-L1; UPS; deep brain stimulation; genome-wide association studies; glucocerebrosidase; human leukocyte antigen; interleukin; leucine-rich repeat kinase 2; lipopolysaccharide; lysosome-associated membrane protein type 2A; mitochondrial DNA; monoamine oxidase-B; mtDNA; nonmotor symptoms; peroxisome proliferator-activated receptor γ coactivator-1α; phosphatase and tensin homolog-inducible kinase 1; substantia nigra pars compacta; subthalamic nucleus; tumor necrosis factor-α; ubiquitin carboxyl-terminal hydrolase L1; ubiquitin–proteasome system

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