Transcript Parkinsons_Mouse_Presentation

α-synuclein
transgenic mouse models
of Parkinson’s disease
Michelle Maurer
December 2015
Parkinson’s disease (PD)
• Described by James Parkinson in 1817
• Symptoms: muscle rigidity, bradykinesia, rest tremor,
postural instability
• Second most common neurodegenerative disorder
after Alzheimer’s disease
• Between 4.1 and 4.5 Million people over 50 affected
worldwide in 2005
Parkinson’s disease (PD)
5 - 20% familial
(= family history of PD)
Sporadic/
Idiopathic
genetic risk factors/
environmental factors/
life style
Caused by genes of the
PARK-family among others
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Parkinson’s disease (PD)
5 - 20% familial
(= family history of PD)
Sporadic/
Idiopathic
genetic risk factors/
environmental factors/
life style
Caused by genes of the
PARK-family among others
28 distinct chromosomal regions more or less related to PD
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Parkinson’s disease (PD)
Pathology – Lewy bodies
Striatum
= Substantia
nigra pars
compacta
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Parkinson’s disease (PD)
Pathology – Lewy bodies
Striatum
= Substantia
nigra pars
compacta
1
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Parkinson’s disease (PD)
Stages
2
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Parkinson’s disease (PD)
Stages
2
Standard drug since 1961: L-DOPA
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Mouse models for PD research
1.) Toxin and pharmacological models
2.) Genetic models
3.) Others
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Genetic models
Autosomal dominant PD Genes:
• SNCA/PARK1/PARK4: α-synuclein
• LRRK2/PARK8: leucine-rich repeat kinase 2
Autosomal recessive PD genes:
• Parkin/PARK2: E3 ubiquitin ligase
• PINK1/PARK6: PTEN-induced putative kinase 1
• DJ-1/PARK7: Parkinson protein 7
• (ATP13A2/PARK9: ATPase type 13A2)
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Genetic models
Autosomal dominant PD Genes:
• SNCA/PARK1/PARK4: α-synuclein
• LRRK2/PARK8: leucine-rich repeat kinase 2
Autosomal recessive PD genes:
• Parkin/PARK2: E3 ubiquitin ligase
• PINK1/PARK6: PTEN-induced putative kinase 1
• DJ-1/PARK7: Parkinson protein 7
• (ATP13A2/PARK9: ATPase type 13A2)
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α-synuclein (α-syn)
• Highly conserved among vertebrates
• Primarily found in the brain, but also other tissues
• Exact physiological function still unknown, but
probably involved in dopamine release
• Located in presynaptic terminals
• Interacts with lots of proteins,
lipids and mitochondria
• In PD patients:
Aggregation in Lewy bodies as fibrils
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Aggregation of α-syn
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Cell-to-cell
transmission of
α-syn
2
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Mutations of α-syn
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•
•
•
140 amino acids
Five known mutations at the N-terminal
Duplications and triplications
No mutations in majority of PD patients
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Mouse VS Human
• Human and mouse α-syn are 95.3% identical
• 7 amino acids differ
• Human mutation A53T represents WT mouse
sequence
• Differences in non-coding regions of SNCA
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Transgenic mouse models of α-syn
Aim: generating a mouse model that shows all PD
characteristics to develop and test drugs
Typical PD features:
• Lewy body formation with fibrils
• Neuronal cell loss in basal ganglia
• Age-related disease progression
• Motor-symptoms
• Non-motor symptoms
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Transgenic mouse models of α-syn
• In 1997: first human mutation in α-syn was
discovered (A53T)
• First mouse model in 2000
• Since then: 28 models
• Based on 12 “basic” models
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Outcome of α-syn models
• Some mouse models show PD features (inclusions,
motor deficits, neuronal cell loss)
• Contribution to knowledge about α-syn:
- presynaptic regulator of dopamine
transmission
- Interaction with Rab – proteins
- Bound to mitochondria
- Ability to spread
- Direct transfer from neurons to astrocytes
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Limitations
• Mice do not develop PD naturally
• No mouse model is able to show all human PD
characteristics
• Different phenotypes due to the use of different
promoters and strain backgrounds of the mice
SNCA
• Motor neurons are affected, which is not a feature of
human PD
• Human and mouse protein interfere with each other
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Summary
• Many limitations and very little outcome
• Most important discoveries about PD were made in
human based or in vitro studies
- protein and gene structure
- mutations of SNCA
- cellular function
→ transgenic mouse models are not very valuable for
α-syn research
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References
1 Dauer, W. (2003). Parkinson’s Disease. Neuron, 39(6), 889–909.
2 Brettschneider, J. (2015). Spreading of pathology in neurodegenerative diseases: a
focus on human studies. Nature Reviews Neuroscience, 16(2), 109–120.
3 https://en.wikipedia.org/wiki/Chemical_synapse
4 Dehay, B. (2015). Targeting α-synuclein for treatment of Parkinson’s disease:
mechanistic and therapeutic considerations. The Lancet Neurology, 14(8),
855–866.
5 Appel-Cresswell, S. (2013). Alpha-synuclein p.H50Q, a novel pathogenic mutation
for Parkinson’s disease. Movement Disorders, 28(6), 811–813.
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