Shaping the Future: Research Updates and Clinical Application for Parkinson's Disease
Pathophysiology of Parkinson’s Disease
Ted M. Dawson, M.D., Ph.D. Director, Institute for Cell Engineering Director, Morris K. Udall Parkinson's Disease Research Center Leonard and Madlyn Abramson Professor in Neurodegenerative Diseases Professor, Departments of Neurology, Neuroscience and Pharmacology & Molecular Sciences PARkinson’s Disease cost exceeds 0.5-1.5 MILLION PEOPLE ~50,000 USA new cases $14.4 BILLION are reported annually each year Treatments: Drug therapy and deep-brain stimulation Average age ILLION PEOPLE to alleviate symptoms, but ~6 M of onset Worldwide not causes. 60 yo Onset as early
2 yo Appears to be slightly more
common in men than women2040 Both prevalence and Expectation of a doubling of incidence increase Parkinson’s patients and costs by with advancing age Hallmark Neuropathology of Parkinson’s disease PMID: 23183883 Neurology volume9, pages 13 100 yearspathology.Lewy of Nature Reviews , Neuron Neuron , PMID: 12971891 PMID: – Review Review 24 (2013) Dauer & Przedborski 2003 Parkinson’s disease is more than a Movement Disorder – Braak Staging PMID: 23183883 Neurology volume9, pages 13 100 yearspathology.Lewy of Nature Reviews – 24 (2013)
https://en.wikipedia.org/wiki/Braak_staging PARkinson’s Disease Is More Than A Movement Disorder
Intracytoplasmic inclusions termed Lewy bodies containing α-synuclein. • REM Sleep BD Stooped posture • Anxiety Rigid limbs, Hyposmia • Depression Slow movement Reduced facial Substantia nigra not first site of • Dementia expressions injury in PD, Lewy neurites found (bradykinesia) in olfactory bulb & autonomic Speech nervous system. impairments Widespread Inability to move neuropathology (akinesia) Heart Rate through multiple Variability neuronal systems. Postural instability, loss of balance Often, the first diagnosed symptom of Parkinson’s Sexual difficulties disease is tremor (trembling or shaking) of a limb. Constipation Shuffling gait
Severity progresses over time Propagation and Transmission of Pathogenic Proteins
Donor
Misfolded Normal α-synuclein α-synuclein (monomer)
Ulmer et al. PDB ID:1XQ8 Collection of fibrils PMID: 15615727 forms Lewy body
Aggregation of misfolded α-synuclein (oligomer) Tuttle et al., PDB ID:2N0A, PMID:27018801 Assembly of misfolded Recipient α-synuclein into fibrils LAG3 is required for pathologic α-Syn transmission and cell death X. Mao et al., Science 353, aah3374 (2016). DOI: 10.1126/science.aah3374 LAG3 is required for a-Syn PFF mediated neurodegeneration of dopamine neurons in vivo Pathways of Neurodegeneration in PARkinson’s Disease
Yun et al. Nature Medicine (2018) https://doi.org/10.1038/s41591-018-0051-5 NLY01 blocks -Syn PFF loss of Dopamine Neurons and Behavioral Deficits
A 𝛂𝛂 B
C D E Pathways of Neurodegeneration in PARkinson’s Disease
Yun et al. Nature Medicine (2018) https://doi.org/10.1038/s41591-018-0051-5 Key players in neuronal death – past and future
PMID: 29362479 PAR Signaling PARthanatos (PARP-1-Dependent Cell Death)
PNAS 88:6368-6371 (1991) J. Neurosci. 13: 2651-2661 (1993) Science 263: 687-689 (1994) Nature Med. 3: 1089-1095 (1997) Science 297:259-263 (2002) J. Neurosci. 24: 10963-10973 (2004) PNAS, 103: 18308-18313 (2006) PNAS, 103: 18314-18319 (2006) Neuroscience 148: 198-211 (2007) ASN Neuro. 1(5). Pii:e00021. doi:10.1042/AN20090046 (2009) J. Neurochem. 110:687-696 (2009) J. Neurochem. 113:1012-22 (2010) Sci Signal. 4(167):ra20 (2011) Nature Med. 17(6):692-9 (2011) PNAS 23:108(34):14103-8 (2011) Nature Neurosci. 16:1392-1400(2013) PNAS 111:10209-14 (2014) Sci Transl Med Apr 6;8(333):333ra48 (2016) Science Oct 7;354(6308) (2016) α-Syn PFF-induced dopaminergic deficits are reduced by deletion of PARP-1 or the PARP inhibitor, ABT-888 PAR accelerates α-Syn fibrillization PAR binding to α-Syn generates a PAR-PFF α-Syn strain that accelerates dopaminergic toxicity in vivo Increase of PAR levels in the CSF of patients with PARkinson’s Disease Pathways of Neurodegeneration in PARkinson’s Disease Pathways of Neurodegeneration in PARkinson’s Disease and Therapies Johns Hopkins University Acknowledgments Institute For Cell Engineering Han Seok Ko Johns Hopkins University~Dawson Sueng Pil Yun Labs Neuropathology Juan Troncoso Valina L. Dawson Olga Pletikova Neurology Shaida Andrabi Liana Rosenthal Saurav Brahmachari Alexander Pantelyat Cleveland Clinic Rong Chen Lynn M. Berkis Shih-Ching Chou James B. Leverenz Tae-in Kam University of Laval Senthil Karuppagounder Guy B. Poirier Stanford Xiaobo Mao Shane Liddelow Hyejin Park Ben Barres Nikhil Panicker Disclosures: Drs. Dawson are an inventors of technology discussed in Chen Qi this presentation, which Neuraly, Inc. George Umanah has licensed from Johns Hopkins I-Hsun Wu University. Drs. Dawson are founders Supported of, and hold shares of stock options as well as equity in, Neuraly, Inc. Drs. by Dawson are founders of Valted, LLC NIH/NINDS/NIDA/ and holds an ownership equity interest in the company. Drs. NIA Dawson are consultants to JPB Inhibikase Therapeutics and own stock options in the company. These MJFF arrangements have been reviewed AHMMRF and approved by the Johns Hopkins University in accordance with its DHHMRF conflict of interest policies. CPT