I lead a research team in HKU focusing mainly on Parkinson's disease (PD), its etiology, pathogenesis and exploring therapeutic methods to modify these processes. Our earlier research described how a ubiquitous xenobiotic enzyme, catechol-O-methyltransferase (COMT) provided the link between the effects of estrogen and PD. This project delivered tangible materials including human COMT antibodies and a patented COMT ELISA assay containing a unique synthetic 18 amino acid polypeptide protein tag. This enzyme assay can quantify the estrogenic effects of environmental pollutants, such as PCBs and plasticizers linked to cancer and neurodegeneration. We have previously explored mitochondrial dysfunction, an important pathogenic process involved in PD. We described and elucidated some of the neuroprotective mechanisms of mitochondrial neuronal uncoupling proteins (UCPs) in experimental models of PD. We have developed methods and materials including antibodies to human neuronal uncoupling proteins (UCP4 and 5). Our studies uncovered a novel link between UCPs and nuclear-factor kappa-B (NF-kB), and more specifically the c-Rel pro-survival pathway, which can be a potential therapeutic target in PD. In parallel studies, we described the beneficial effects of leptin (a regulator of metabolism) on neuronal survival being mediated via UCP2, supporting a link between metabolic pathways and pathogenic processes in PD. We also elucidated how UCP4 interacted with mitochondrial Complex II to preserve ATP synthesis under cellular stress.
More recently, we have developed a unique colony of an experimental mouse model with a leucine-rich repeat kinase-2 (LRRK2) knockin mutation (C57BL/6N background) based on the mutation found in familial PD. Our current work focuses on pathogenic mechanisms and developing therapeutic methods to modify the course of LRRK2-related and sporadic idiopathic PD. One key aim is to deliver unique materials in unraveling the pathogenic processes of PD, in particular developing novel methods to assay the rates of different forms of autophagy.
- Klionsky DJ, Abdel-Aziz AK, Abdelfatah S,…Leung GCT,…Liu HF…,Ho, PWL, Ho SL,… Ramsden DB…Sluimer JC, Stallings CL, Tong CK. Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition). Autophagy. 2021 Jan;17(1):1-382. doi: 10.1080/15548627.2020.1797280. Epub 2021 Feb 8.
- Liu HF, Ho PWL, Leung CT, Pang SY, Chang EES, Choi ZY, Kung MH, Ramsden DB, Ho SL. Aberrant mitochondrial morphology and function associated with impaired mitophagy and DNM1L-MAPK/ERK signaling are found in aged mutant Parkinsonian LRRK2 R1441G mice. Autophagy. 2020 Dec 10:1-25. doi: 10.1080/15548627.2020.1850008.
- Pang SYY, Ho PWL, Liu HF, Leung CT, Li LF, Chang EES, Ramsden DB, Ho SL. The interplay of aging, genetics and environmental factors in the pathogenesis of Parkinson’s disease. Translational Neurodegeneration. 2019 Aug 16;8:23. doi: 10.1186/s40035-019-0165-9. eCollection 2019.
- Ho PWL, Leung MCT, Liu HF, Pang SYY, Lam CSC, Xian JW, Li LF, Kung MHW, Ramsden DB, Ho SL. (2019) Age-dependent accumulation of oligomeric SNCA/α-synuclein from impaired degradation in mutant LRRK2 knockin mouse model of Parkinson's disease: role for therapeutic activation of chaperone-mediated autophagy (CMA). Autophagy. 2019 Apr 14:1-24. doi: 10.1080/15548627.2019.1603545.
- Lis P, Burel S, Steger M, Mann M, Brown F, Diez F, Tonelli F, Holton JL, Ho PW, Ho SL, Chou MY, Polinski NK, Martinez TN, Davies P, Alessi DR. (2018) Development of phospho-specific Rab protein antibodies to monitor in vivo activity of the LRRK2 Parkinson's disease kinase. Biochem J. 2018 Jan 2;475(1):1-22. doi: 10.1042/BCJ20170802.
- Pang SY, Teo KC, Hsu JS, Chang RSK, Li MX, Sham PC, Ho SL. (2017) The role of gene variants in the pathogenesis of neurodegenerative disorders as revealed by next generation sequencing studies: a review. Translational Neurodegeneration. 6:27. doi: 10.1186/s40035-017-0098-0.
- Pang SY, Hsu JS, Teo KC, Li Y, Kung MHW, Cheah KSE, Chan D, Cheung KMC, Li MX, Sham PC, Ho SL. (2017) Burden of rare variants in ALS genes influences survival in familial and sporadic ALS. Neurobiol Aging. 2017 Oct;58:238.e9-238.e15. doi: 10.1016/j.neurobiolaging. 2017.06.007.
- Liu HF, Ho PW, Leung GC, Lam CS, Pang SY, Li L, Kung MH, Ramsden DB, Ho SL. (2017) Combined LRRK2 mutation, aging and chronic low dose oral rotenone as a model of Parkinson's disease. Scientific Reports. 7:40887. doi: 10.1038/srep40887.
- Ito G, Katsemonova K, Tonelli F, Lis P, Baptista M, Shpiro N, Duddy G, Wilson S, Ho PW, Ho SL, Reith AD, Alessi D. (2016) Phos-tag analysis of Rab10 phosphorylation by LRRK2: a powerful assay for assessing kinase function and inhibitors. Biochemical Journal. 473(17):2671-85.
- Liu HF, Lu S, Ho PWL, Tse HM, Pang SYY, Kung MHW, Ho JWM, Ramsden DB, Zhou ZJ, Ho SL. (2014) LRRK2 R1441G mice are more liable to dopamine depletion and locomotor inactivity. Annals of Clinical and Translational Neurology. 1(3):199-208..
|Project Title||Funding Scheme||Amount (HKD)|
|Pathophysiological study of Parkinson's disease associated with leucine-rich repeat kinase 2 (LRRK2) gene mutation||Health and Medical Research Fund (HMRF), Food & Health Bureau, HKSAR Government (August 2013)||$928,040|
|Therapeutic effects of Saracatinib to prevent accumulation of alpha synuclein in Parkinson’s disease.||AstraZeneca Open Innovation (June 2017)||$327,750|
|Therapeutic effects of brain-penetrable inhibitors to prevent accumulation of pathogenic alpha-synuclein oligomers in Parkinson's disease.||Health and Medical Research Fund (HMRF), Food & Health Bureau, HKSAR Government (Jan 2018)||$1,175,760|
|Pathophysiological study of synaptic vesicle protein synaptogyrin3 (SYNGR3) in Parkinson's disease.||Health and Medical Research Fund (HMRF), Food & Health Bureau, HKSAR Government ($1,195,760)||$1,195,760|
|Defective autophagic clearance of damaged mitochondria (mitophagy) as potential therapeutic target of Parkinson’s||Health and Medical Research Fund (HMRF). HKSAR Government (March 2019)||$1,469,224|
- Founding Director & Chairperson, Hong Kong Parkinson's Disease Foundation (2002 to date).
- Chairperson, Advisory Committee, Dept of Rehabilitation Sciences, Polytechnic University, Hong Kong (2014 to date)
Editorial Board Memberships
- Clinical Neuropharmacology, Editorial Board Member (2006-2008), Associate Editor, (2008 to date)
- Brain and Behavior, Editorial Board Member (2011 to date)
- Translational Neurodegeneration, Editorial Board Member (2011 to date)
Human catechol-O-methyltransferase (COMT) assay. Listed inventors: PWL Ho, DB Ramsden, SL Ho.
- US patent granted on 6th January 2015; patent no. US 8,927,225 B2
- China patent granted on 12th November 2014; patent no. ZL 200980138401.0
- European patent granted on 23rd October 2013; patent no. 2328909