Hanseok Ko, PhD

Primary Academic Title

Professor of Neurology

Background

Centers and Institutes

Cell Engineering, Institute for

LinkedIn

https://www.linkedin.com/in/hanseokko/

Recent News Articles and Media Coverage

• Neuraly Announces First Patient Dosed in Phase 2 Clinical Trial of NYL01 for Patients with Parkinson’s Disease, BioSpace (March 03, 2020)

  New mouse model of Parkinson's disease shows how it spreads from the gut, ScienceDaily (June 26, 2019)

  In PD Model, α-Synuclein Spreads from Intestine to Brain, Alzforum (July 12, 2019)

  Nano-size Quantum Dots Bust Up Synuclein Pathology, Alzform (July 13, 2018)

  Does Taming Killer Astrocytes Spare Neurons in Parkinson’s Disease? Alzforum (June 13, 2018)

  Immune Receptor May Smuggle α-Synuclein into Neurons, Hasten Proteopathy, Alzforum  (October 01, 2016)

   

Contact for Research Inquiries

Phone: (410) 502-5454
Fax: (410) 614-9568
hko3@jhmi.edu

Research Interests

Molecular Signals Controlling Neurodegeneration, Parkinson's disease

Research Summary

The Ko lab is currently researching the biology and pathobiology of the proteins and mutant proteins linked to Parkinson’s disease (PD) and Dementia Lewy bodies (DLB). The studies below provide major insights into understanding the pathogenesis of neurologic disorders and have led to the discoveries of the therapies aimed at preventing neurodegenerative disorders.

The team has showed that c-Abl is active in PD and contributes to pathogenesis of PD through tyrosine phosphorylation of α-synuclein and parkin; they have also shown that genetic depletion and pharmacological inhibition of c-Abl protects against α-synuclein-induced neurodegeneration. They are investigating potentially safer and more effective c-Abl inhibitor drug options in mouse models of PD in collaboration with 1stbio therapeutic Inc and Neuraly, Inc.

The team has discovered that LAG3 is the major internalization receptor for pathological α-synuclein that has important implications in PD and DLB. They are investigating the role of APLP-1/LAG3 complex on cell-to-cell transmission of pathologic α-synuclein.

Recently, the team has discovered that pathologic α-synuclein activates microglia converting astrocytes to neurotoxic reactive astrocytes, which kill neurons. Also, they have recently showed that a potent, brain penetrant long-acting glucagon like peptide-1 receptor (GLP-1R) agonist NLY01 protects against neurodegeneration and behavioral deficits in mouse models of PD and AD via the direct prevention of microglial mediated conversion of astrocytes to a reactive astrocyte phenotype. The drug NLY01 is under clinical phase 2 trials for PD and AD patients. 

The team has discovered that microglial NOD2/RIPK2 could be a key regulator driving neurodegeneration induced by pathologic α-synuclein. Genetic deletion and pharmacological inhibition of NOD2/RIPK2 signaling protects against neurodegeneration in PD and AD. They are investigating potentially safer and more effective RIPK2 inhibitor drug options in mouse models of PD, AD, and ALS in collaboration with 1stbio therapeutic Inc and Neuraly, Inc.

The team has been investigating how glucocerebrosidase 1 (GCase) is dysregulated in sporadic PD and GBA1-linked PD. They have discovered TRIP12, a ubiquitin E3 ligase, as a major regulator of wt GCase turnover. They have also uncovered that TRIP12 tightly controls the GCase level via the ubiquitin-proteasome system (UPS), and TRIP12-induced ubiquitination and subsequent degradation of GCase lead to mitochondrial dysfunction. Depleting TRIP12 in the human dopaminergic neurons and SN provides neuroprotection against α-synuclein preformed fibrils-provoked PD by increasing the GCase activity. This study offers novel therapeutic strategies to restore GCase activity and reverse PD. They are identifying agents that inhibit GBA1:Trip12 interaction or inhibit Trip12 E3 ligase activity.

The team has been contributing to establish mouse models of PD. Recently, they have developed a mouse model that supports the Braak’s theory that PD could start in the gut and spread to the brain via the vagus nerve to cause PD. This new model recapitulates the clinical syndrome and manifestations of idiopathic PD including both motor and non-motor symptoms. They are dissecting the circuits involved in the transmission of α-synuclein from the gut to brain. They are also characterizing E326K GBA1 KI mouse line, TH-tTA/D620N VPS35 Tg mouse line, and E326KGBA1/APOE4 KI mouse line.

Google Scholar

https://scholar.google.com/citations?user=Z8MCpfMAAAAJ&hl=en

PubMed

https://pubmed.ncbi.nlm.nih.gov/?term=han+seok+ko&sort=date

Selected Publications

• Kim D, Yoo JM, Hwang H, Lee J, Lee SH, Yun SP, Park MJ, Lee M, Choi S, Kwon SH, Lee S, Kwon SH, Kim S, Park YJ, Kinoshita M, Lee YH, Shin S, Paik SR, Lee SJ, Lee S, Hong BH*, Ko HS*. Graphene quantum dots prevent α-synucleinopathy in Parkinson's disease. Nat Nanotechnol. 2018 Sep;13(9):812-818.

• Kim S, Kwon SH, Kam TI, Panicker N, Karuppagounder SS, Lee S, Lee JH, Kim WR, Kook M, Foss CA, Shen C, Lee H, Kulkarni S, Pasricha PJ, Lee G, Pomper MG, Dawson VL, Dawson TM*, Ko HS*. Transneuronal Propagation of Pathologic α-Synuclein from the Gut to the Brain Models Parkinson's Disease. Neuron. 2019 Aug 21;103(4):627-641.e7.

• Mao X, Ou MT, Karuppagounder SS, Kam TI, Yin X, Xiong Y, Ge P, Umanah GE, Brahmachari S, Shin JH, Kang HC, Zhang J, Xu J, Chen R, Park H, Andrabi SA, Kang SU, Gonçalves RA, Liang Y, Zhang S, Qi C, Lam S, Keiler JA, Tyson J, Kim D, Panicker N, Yun SP, Workman CJ, Vignali DA, Dawson VL*, Ko HS*, Dawson TM*. Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science. 2016;353(6307). *Co-corresponding author. Recommended by F1000 prime

• Seo BA, Kim D, Hwang H, Kim MS, Ma SX, Kwon SH, Kweon SH, Wang H, Yoo JM, Choi S, Kwon SH, Kang S, Kam TI, Kim K, Karuppagounder SS, Kang BK, Lee S, Park H, Kim S, Yan W, Li YS, Kuo SH, Redding-Ochoa J, Pletnikova O, Troncoso JC, Lee G, Mao X, Dawson VL, Dawson TM, and Ko HS. TRIP12 Ubiquitination of Glucocerebrosidase Contributes to Neurodegeneration in Parkinson’s Disease. Neuron. 2021 Dec 1;109(23):3758-3774.e11.

• Yun SP, Kam TI, Panicker N, Kim S, Oh Y, Park JS, Kwon SH, Park YJ, Karuppagounder SS, Park H, Kim S, Oh N, Kim NA, Lee S, Brahmachari S, Mao X, Lee JH, Kumar M, An D, Kang SU, Lee Y, Lee KC, Na DH, Kim D, Lee SH, Roschke VV, Liddelow SA, Mari Z, Barres BA, Dawson VL, Lee S*, Dawson TM*, Ko HS*. Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson's disease. Nat Med. 2018 Jul;24(7):931-938.

Patents

• Transcriptional repression leading to parkinson's disease, US Patent 9,274,128
• Therapeutic Uses of Lag3 the (alpha)-Synuclein Transmission Receptor, US Patent App. 16/327,046
• Long-acting glp-1r agonist as a therapy of neurological and neurodegenerative conditions, U.S. Patent No. 11,123,405
• Inhibition of rip kinases for treating neurodegenerative disorders, US Patent App. 17/271,966
• Graphene nanostructure-based pharmaceutical composition for preventing or treating neurodegenerative diseases, US Patent 10,772,910

Honors

• AKN Jr Faculty Award, Association of Korean Neuroscientists
• Maryland Innovation Initiative (MII) Award, TEDCO
• Discovery fund Innovation Award, JHU
• NETP Investigator-Initiated Research Award, Department of Defense office (DOD), 1/1/21
• Highly Cited Researcher, Clarivate Web of Science, 1/1/21
• Discovery Innovation Award, The Johns Hopkins University School of Medicine, 11/11/17
• Award for President's Outstanding Research, Association of Korean Neuroscientists (AKN), 1/1/05

Memberships

• Association of Korean Neuroscientists (AKN), Council Member
• Baltimore Life Scientists Association (BLSA)
• Korean-American Scientists and Engineers Association (KSEA)
• Society for Neuroscience (SFN)

Additional Training

The Johns Hopkins School of Medicine, Baltimore, MD, 2008, Neurobiology (Postdoc training)