Parkinson’s Disease: Etiology and Molecular Mechanismsm-learning.zju.edu.cn/G2S/eWebEditor/uploadfile/20131220113204209.pdf · neurotoxin precursor to MPP+, which causes permanent

Parkinson’s Disease: Etiology and Molecular Mechanisms

Binggui Sun Institute of Neuroscience

[email protected]

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)

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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!