1. α-synuclein transgenic mouse models of Parkinson’s disease Michelle Maurer December 2015

2. 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

3. Parkinson’s disease (PD) 5 - 20% familial (= family history of PD) Sporadic/ Idiopathic Caused by genes of the PARK-family among others genetic risk factors/ environmental factors/ life style 3

4. Parkinson’s disease (PD) 5 - 20% familial (= family history of PD) Sporadic/ Idiopathic Caused by genes of the PARK-family among others genetic risk factors/ environmental factors/ life style 28 distinct chromosomal regions more or less related to PD 4

5. Parkinson’s disease (PD) Pathology – Lewy bodies Substantia nigra pars compacta = Striatum 5 1

6. Parkinson’s disease (PD) Pathology – Lewy bodies Substantia nigra pars compacta = Striatum 6 1

7. Parkinson’s disease (PD) Stages 7 2

8. Standard drug since 1961: L-DOPA 8 2

9. Mouse models for PD research 1.) Toxin and pharmacological models 2.) Genetic models 3.) Others 9

10. 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) 10

11. 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) 11

12. 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 12 3

13. Aggregation of α-syn 13 4

14. Cell-to-cell transmission of α-syn 14 2

15. Mutations of α-syn 140 amino acids Five known mutations at the N-terminal Duplications and triplications No mutations in majority of PD patients 15 5

16. 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 16 5

17. 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 17

18. 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 18

19. 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 19

20. 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 Motor neurons are affected, which is not a feature of human PD Human and mouse protein interfere with each other 20 SNCA

21. 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 21

22. 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. 22