Parkinson’s Disease: Etiology and Molecular...
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Parkinson’s Disease: Etiology and Molecular Mechanisms Binggui Sun Institute of Neuroscience [email protected]
Transcript of Parkinson’s Disease: Etiology and Molecular...
Parkinson’s Disease: Etiology and Molecular Mechanisms
Binggui Sun Institute of Neuroscience
Clinical Features of PD
James Parkinson 1817
Clinical Features of PD
Anatomical Changes in PD Loss of dopaminergic neurons in the substantia nigra pars compacta(SNpc)
Anatomical Changes in PD Loss of dopaminergic neurons in the substantia nigra pars compacta(SNpc)
Arvid Carlsson
Dr. Carlsson discovered in 1958 that dopamine is a neurotransmitter in the brain and that it has great importance for our ability to control movements
Anatomical Changes in PD N
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Basal Ganglion
Loss of Dopamine Neurons in Parkinson’s Disease
Loss of Dopamine Neurons in Parkinson’s Disease
Etiology of Parkinson’s Disease
• Environmental toxin hypothesis
• Genetic hypothesis
• Gene vulnerability hypothesis
Etiology of Parkinson’s Disease
• Environmental toxin hypothesis
MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine): a
neurotoxin precursor to MPP+, which causes permanent symptoms of Parkinson's disease by destroying dopaminergic neurons in the substantia nigra of the brain.
Toxicity of MPTP in Mice
Nature Protocols, 2007
Etiology of Parkinson’s Disease
• Environmental toxin hypothesis
MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine): a
neurotoxin precursor to MPP+, which causes permanent symptoms of Parkinson's disease by destroying dopaminergic neurons in the substantia nigra of the brain.
Rotenone: pesticide 鱼藤酮 Paraquat: herbicide 百草枯 Maneb: fungicide 代森锰
Etiology of Parkinson’s Disease
• Genetic hypothesis
SNCA: encoding α-synuclein PARK2: encoding the E3 ubiquitin ligase parkin PARK6: encoding PINK1,a mitochondrial kinase PARK7: encoding the protein DJ-1 PARK8: encoding leucine-rich repeat kinase 2 (LRRK2) PARK9: encoding ATP13A2
Genetic mutations or duplications account for only 3-5% of all PD cases
However:
Etiology of Parkinson’s Disease
• Gene vulnerability hypothesis
Pathogenesis of Parkinson’s Disease
• Disruption of protein quality control
• Mitochondrial dysfunction
• Oxidative stress
• Inflammation
Pathogenesis of Parkinson’s Disease
• Disruption of protein quality control
Misfolding of proteins
Pathogenesis of Parkinson’s Disease
• Disruption of protein quality control
Misfolding of proteins
Pathogenesis of Parkinson’s Disease
• Disruption of protein quality control
Misfolding of proteins
Mahley, Neuron (2012)
Pathogenesis of Parkinson’s Disease
• Disruption of protein quality control
Misfolding of proteins Abnormal accumulation (Increase in production & deficits in clearance)
Pathogenesis of Parkinson’s Disease
• Disruption of protein quality control
Misfolding of proteins Abnormal accumulation (Increase in production & deficits in clearance)
UPS: ubiquitin proteasome system
Pathogenesis of Parkinson’s Disease
• Disruption of protein quality control
Misfolding of proteins Abnormal accumulation (Increase in production & deficits in clearance)
UPS: ubiquitin proteasome system Autophagy
Pathogenesis of Parkinson’s Disease
• Disruption of protein quality control
Misfolding of proteins Abnormal accumulation (Increase in production & deficits in clearance)
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Pathogenesis of Parkinson’s Disease
• Disruption of protein quality control
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Misfolding of proteins Abnormal accumulation (Increase in production & deficits in clearance)
Chem
Bio
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Pathogenesis of Parkinson’s Disease
• Disruption of protein quality control
Misfolding of proteins Abnormal accumulation (Increase in production & deficits in clearance)
Soluble oligomers are more toxic!
Pathogenesis of Parkinson’s Disease
• Disruption of protein quality control
• Mitochondrial dysfunction
• Oxidative stress
• Inflammation
Schematic Representation of Mitochondrial Compartmentalization
Mitochondrial Dysfunction in PD
Pathogenesis of Parkinson’s Disease
• Disruption of protein quality control
• Mitochondrial dysfunction
• Oxidative stress
• Inflammation
A unifying role for prions in neuro- degenerative diseases Prusiner SB, Science 2012, 336:1511-1513
A unifying role for prions in neuro- degenerative diseases Prusiner SB, Science 2012, 336:1511-1513
Stanley B. Prusiner
Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice
Luk KC, et al., Science 2012
Further reading if you are interested in Parkinson’s disease
Thank You!
