THE KO LAB

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 therapies aimed at preventing neurodegenerative disorders.

The team is investigating potentially safer and more effective c-Abl inhibitor drug options in mouse models of PD. We determined that LAG3 is the major internalization receptor for pathological α-synuclein that has important implications in PD and DLB. We are currently investigating the role of APLP-1/LAG3 complex on the cell-to-cell transmission of pathologic α-synuclein.

Recently, we discoverd that pathologic α-synuclein activates microglia and converts astrocytes into neurotoxic reactive astrocytes, which kill neurons. Also, we have shown 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. NLY01 is under clinical phase 2 trials for PD and AD patients. 

We have determined 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 protect against neurodegeneration. We are investigating potentially safer and more effective RIPK2 inhibitor drug options in mouse PD, AD, and ALS models. In addition, we have been investigating how glucocerebrosidase 1 (GCase) is dysregulated in sporadic PD and GBA1-linked PD.

We discovered TRIP12, a ubiquitin E3 ligase, as a major regulator of wt GCase turnover. We 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.

Finally, we have been collaborating to establish mouse models of PD. We developed a mouse model that supports 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. We are currently dissecting the circuits involved in the transmission of α-synuclein from the gut to the brain and characterizing the E326K GBA1 KI mouse line, TH-tTA/D620N VPS35 Tg mouse line, and E326KGBA1/APOE4 KI mouse line.