1. c-Abl activation: the search for a unifying disease pathway in Parkinson’s disease
Preston Ge
Institute for Cell Engineering
Johns Hopkins School of Medicine

2. PD is a widespread, debilitating neurodegenerative disease
Epidemiology
Parkinson’s is the most common motor neurodegenerative disease in the world.
Economic burden exceeds $14.4 billion in the U.S. alone ($22,800 per patient).
Core Symptoms
Motor: resting tremor, limb stiffness, poverty of movement, reduced amplitude and quality of movement.
Non-motor: sleep disturbances, affective flattening, cognitive decline and dementia, depression.
Image courtesy of Parkinson’s Disease Foundation

3. Dauer and Przedborski (2003)
Pathophysiology of PD
Cellular Pathology of PD
Selective degeneration of dopamine (DA) neurons in the Substantia Nigra pars compacta (SNpc).
Late stage: more widespread neurodegeneration.
Molecular Pathology of PD
Hyper-phoshorylated ubiquitin and α-synuclein-rich intracellular inclusion bodies (Lewy Bodies) distributed throughout the SNpc.
Dauer and Przedborski (2003)

4. Protein aggregation and mitochondrial defects are crucial disease pathways
α-synuclein aggregation
Observed in vast majority of sporadic and familial cases.
Has been linked as the cause of many downstream neurotoxic pathways.
Mitochondrial dysfunction
Mitochondrial toxins selectively kill SNpc DA neurons.
Many PD-linked gene variants disrupt mitochondrial function.
Irwin, Lee, and Trojanowski (2013)
Zuo and Motherwell (2013)

5. Genetics of Parkinson’s disease suggest core pathological pathways and interactions
Additional linked loci
VPS35
Impairs mitochondrial fusion and function (Tang et al, 2015).
Glucocerebrosidase (GBA)
?? Pathological interaction with α-syn ?? (Mazulli et al, 2011).
Mitochondria
α-synuclein
Both
Pissl and Winklhofer (2011)

6. Our current model for the c-Abl neurotoxic pathway in PD
c-Abl is a stress-activated kinase that disrupts mitchondrial quality control
Our current model for the c-Abl
neurotoxic pathway in PD
A non-receptor tyrosine kinase activated by oxidative stress.
Autophosphorylation at Y245 or Y412 activates c-Abl.
c-Abl activation is crucial for MPTP-induced neurodegeneration (Ko et al, 2010).
Ko et al (2010), Shin et al (2011), Lee et al (2013), Stevens et al (2015)
Hantschel and Superti-Furga (2004)

7. α-synuclein accumulation activates the c-Abl pathway
MoPrP-hA53T α-synuclein G2 line
Constitutive overexpression of human pathological mutant (hA53T) α-synuclein across the mouse brain.
Cardinal motor symptoms and molecular pathology of PD.
Pathology is observed in the brain, spinal cord, and cerebellum.

13. Clinical implications
First discrete molecular pathway unifying α-synuclein pathology and mitochondrial dysfunction, two essential disease pathways in PD.
c-Abl pathway activation and α-synuclein accumulation seem to form a bidirectional pathological loop that drives molecular pathology and neurodegeneration.

14. Future steps: what is PARIS’s role?
PARIS accumulation and c-Abl activation seem equally necessary for α-synuclein pathology, suggesting that the primary pathological disruptions occur downstream of PARIS accumulation.
PARIS is a zinc-finger transcriptional repressor whose transcriptional regulatory network is mostly unknown.
My current project is to utilize Translating Ribosomal Affinity Purification (TRAP) to isolate mRNA species actively translated in PARIS-KO and PARIS-WT mice with α-synuclein pathology. RNAseq will then be carried out to evaluate pathology-induced changes in the nigral DA neuron translatome.
The extent to which PARIS-KO protects against a-syn toxicity suggests that elements of this network are crucial for α-synuclein-induced neurodegeneration.

15. References
Dauer, W., Przedborski, S. (2003) Parkinson's Disease: Mechanisms and models. Neuron 39,
Hantschel, O., & Superti-Furga, G. (2004). Regulation of the c-Abl and Bcr–Abl Tyrosine Kinases. Nature Reviews Molecular Cell Biology, 5,
Irwin, D., Lee, V., & Trojanowski, J. (2013). Parkinson's disease dementia: Convergence of α-synuclein, tau and amyloid-β pathologies. Nature Reviews Neuroscience, 14,
Ko, H., Lee, Y., Shin, J., Karuppagounder, S., Gadad, B., Koleske, A., Dawson, T. (2010). Phosphorylation by the c-Abl protein tyrosine kinase inhibits parkin's ubiquitination and protective function. Proceedings of the National Academy of Sciences, 107(38),
Kowal, S., Dall, T., Chakrabarti, R., Storm, M., & Jain, A. (2013). The current and projected economic burden of Parkinson's disease in the United States. Movement Disorders, 28(3),
Lee, Y., Karuppagounder, S., Shin, J., Lee, Y., Ko, H., Swing, D., Dawson, T. (2013). Parthanatos mediates AIMP2-activated age-dependent dopaminergic neuronal loss. Nature Neuroscience, 16(10),
Mazzulli, J., Xu, Y., Sun, Y., Knight, A., Mclean, P., Caldwell, G., Krainc, D. (2011). Gaucher Disease Glucocerebrosidase and α-Synuclein Form a Bidirectional Pathogenic Loop in Synucleinopathies. Cell, 146(1),
Pissl, A., & Winklhofer, K. (2011). Parkin, PINK1 and mitochondrial integrity: Emerging concepts of mitochondrial dysfunction in Parkinson's disease. Retrieved November 7, 2015.
Shin, J., Ko, H., Kang, H., Lee, Y., Lee, Y., Pletnikova, O., Dawson, T. (2011). PARIS (ZNF746) Repression of PGC-1α Contributes to Neurodegeneration in Parkinson's Disease. Cell, 144(5),
Stevens, D., Lee, Y., Kang, H., Lee, B., Lee, Y., Bower, A., Dawson, T. (2015). Parkin loss leads to PARIS-dependent declines in mitochondrial mass and respiration. Proceedings of the National Academy of Sciences, 112(37),
Tang, F., Liu, W., Hu, J., Erion, J., Ye, J., Mei, L., & Xiong, W. (2015). VPS35 Deficiency or Mutation Causes Dopaminergic Neuronal Loss by Impairing Mitochondrial Fusion and Function. Cell Reports, 12(10),
Zuo, L., & Motherwell, M. (2013). The impact of reactive oxygen species and genetic mitochondrial mutations in Parkinson's disease. Gene, 532(1),

16. c-Abl phosphorylates α-synuclein
Data courtesy of S. Brahmachari and X. Mao.