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 0.5-1.5 MILLION PEOPLE ~50,000 USA new cases

cost exceeds

$14.4 BILLION

are reported annually

each year

~6 MILLION PEOPLE Worldwide

Treatments: Drug therapy and deep-brain stimulation to alleviate symptoms, but

not causes.

Average age of onset

60

yo

Onset as early

2

Appears to be slightly more

common in men than women

2040

Expectation of a doubling of Parkinson’s patients and costs by

yo

Both prevalence and

incidence increase

with advancing age

100 years of Lewy pathology. Nature Reviews Neurology volume 9, pages 13–24 (2013) PMID: 23183883

Dauer & Przedborski, Neuron 2003 Review PMID: 12971891

Hallmark Neuropathology of Parkinson’s disease

Parkinson’s disease is more than a Movement Disorder – Braak Staging 100 years of Lewy pathology. Nature Reviews Neurology volume 9, pages 13–24 (2013) PMID: 23183883

https://en.wikipedia.org/wiki/Braak_staging

PARkinson’s Disease Is More Than A Movement Disorder Intracytoplasmic inclusions termed Lewy bodies containing α-synuclein.

Hyposmia

Substantia nigra not first site of injury in PD, Lewy neurites found in olfactory bulb & autonomic nervous system.

Heart Rate Variability

• • • •

REM Sleep BD Anxiety Depression Dementia

Widespread neuropathology through multiple neuronal systems.

Stooped posture Slow movement (bradykinesia) Inability to move (akinesia) Postural instability, loss of balance Sexual difficulties

Constipation

Shuffling gait

Severity progresses over time

Rigid limbs, Reduced facial expressions Speech impairments

Often, the first diagnosed symptom of Parkinson’s disease is tremor

(trembling or shaking) of a limb.

Propagation and Transmission of Pathogenic Proteins Donor

Normal α-synuclein

Misfolded α-synuclein (monomer)

Ulmer et al. PDB ID:1XQ8 PMID: 15615727

Collection of fibrils forms Lewy body Aggregation of misfolded α-synuclein (oligomer) Tuttle et al., PDB ID:2N0A, PMID:27018801

Assembly of misfolded α-synuclein into fibrils

Recipient

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

A

C

NLY01 blocks 𝛂𝛂-Syn PFF loss of Dopamine Neurons and Behavioral Deficits B

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

Acknowledgments

Johns Hopkins University~Dawson Labs Valina L. Dawson Shaida Andrabi Saurav Brahmachari Rong Chen Shih-Ching Chou Tae-in Kam Senthil Karuppagounder Xiaobo Mao Hyejin Park Nikhil Panicker Chen Qi George Umanah I-Hsun Wu Supported by NIH/NINDS/NIDA/ NIA JPB MJFF AHMMRF DHHMRF CPT

Johns Hopkins University Institute For Cell Engineering Han Seok Ko Sueng Pil Yun Neuropathology Juan Troncoso Olga Pletikova Neurology Liana Rosenthal Alexander Pantelyat Cleveland Clinic Lynn M. Berkis James B. Leverenz University of Laval Guy B. Poirier Stanford Shane Liddelow Ben Barres Disclosures: Drs. Dawson are an inventors of technology discussed in this presentation, which Neuraly, Inc. has licensed from Johns Hopkins University. Drs. Dawson are founders of, and hold shares of stock options as well as equity in, Neuraly, Inc. Drs. Dawson are founders of Valted, LLC and holds an ownership equity interest in the company. Drs. Dawson are consultants to Inhibikase Therapeutics and own stock options in the company. These arrangements have been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies.