Han Seok Ko, Ph.D., M.S.

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.