• Molecular pathogenesis and therapeutic target identification
• Drug discovery and therapeutic strategies
• Neuroimaging and biomarker identification
• Gene therapy, digital and AI application

Research Projects

• LRRK2 and PD pathogenesis
• AD pathogenesis
• Neurodegeneration and Protein Aggregation in the Pathogenesis of Neurodegenerative Diseases
• Metabolic pathways and obesity
• Neuroimaging and biomarker identification
• Exploring novel treatment strategies

LRRK2 and PD pathogenesis

Our group has discovered that LRRK2 binds with GTP and regulates its kinase activates. We are the first group to report that mutant LRRK2 causes neurodegeneration. We have studied the LRRK2 interaction partners and explored LRRK2-linked pathways in cell death and protein aggregation. We generated the first LRRK2-PD-Drosophila model, LRRK2 transgenic mouse model, and the combined gene/environment interaction mouse models. These LRRK2 based PD models have been widely used by others in the field to study pathogenesis and therapeutics. Our group identified the first generation of LRRK2 GTP binding inhibitors and several LRRK2 kinase inhibitors, which can block LRRK2 GTP binding activity and reduce LRRK2 kinase activity. These LRRK2 inhibitors not only provide pharmacological tools to dissect LRRK2 functions, but also can reduce PD-linked mutant LRRK2-induced neuronal degeneration and neuroinflammation in cultured neurons and in mouse brains of LRRK2 PD models. These LRRK2 inhibitors provide the lead compounds for potential development of disease-modifying therapeutic agents for PD intervention.

• Thomas JM, Li T, Yang W, Xue F, Fishman PS and Smith WW. 68 and FX2149 attenuate mutant LRRK2-R1441C-induced neural transport impairment. Frontiers in Aging Neuroscience. 2017, 10;8:337.
• Li T, Ning B, Kong L, Dai B, He X, Thomas JM, Sawa A, Ross CA, *Smith WW. A LRRK2 GTP binding inhibitor, 68 reduces LPS-induced signaling events and TNF-α release in human lymphoblast. Cells. 2021; 10(2):480.
• Z. Liu, X. Wang, Y. Yu, X. Li, T. Wang, H. Jiang, Q. Ren, Y. Jiao, A. Sawa, T. Moran, C. A. Ross, C. Montell and Smith WW. A Drosophila model for LRRK2-linked Parkinsonism. Proc Natl Acad Sci U S A. 2008, 105(7):2693-8.
• Smith WW, Z. Pei, H. Jiang, VL. Dawson, TM. Dawson, CA. Ross. Kinase activity of mutant LRRK2 mediates neuronal toxicity. Nature Neuroscience, 2006, 9(10):1231-3

AD pathogenesis

We have studied the Aβ-induced neuronal toxicity and its underlying signaling pathways to understand the molecular pathogenesis of AD. We have found that Shc66, JNK, cdk5, and inflammasome pathways play the critical roles in Aβ toxicity underlying AD pathogenesis. We have developed the novel genetic therapy targeting neuroinflammation that attenuated AD pathology in animal models.  Our studies will not only identify molecular therapeutic target (s) but also sink for novel treatment strategies.  

• Lin L, Huang L, Huang S, Chen W, Huang H, Chi L, Su F, Liu X, Yuan K, Jiang Q, Li C, Smith WW, Fu Q, Pei Z. MSC-Derived Extracellular Vesicles Alleviate NLRP3/GSDMD-Mediated Neuroinflammation in Mouse Model of Sporadic Alzheimer's Disease. Mol Neurobiol. 2024 Jan 10. doi: 10.1007/s12035-024-03914-1.
• Smith WW, M. Gorospe, JW. Kusiak. Signaling mechanisms underlying Aβ toxicity: Potential Therapeutic Targets for Alzheimer's Disease. (2006). CNS Neurol Disord Drug Targets.  5(3):355-61. 
• Smith WW, DD. Norton, M. Gorospe, H. Jiang, NJ. Holbrook, S. Nemoto, T. Finkel, J.W. Kusiak. Phosphorylation of p66Shc and forkhead proteins mediates Aβ toxicity. (2005). J Cell Biol. 25;169(2):331-9.

Neurodegeneration and Protein Aggregation in the Pathogenesis of Neurodegenerative Diseases

We have studied the protein-protein interactome and gene change profiles in neurodegeneration using in vitro cell culture and in vivo animal models of PD, AD, HD and related disorders. We have investigated the protein aggregation and clearance pathways to understand the protein inclusion (aggregates) formation in the pathogenesis.  

• Thomas JM, Wang W, Guo G, Li T, Dai B, Sun X, Leslie G. LG, Nucifora Jr. NC1, Liu Z, Xue F, Liu C, Ross CA, Smith WW. GTP-binding Inhibitors Increase LRRK2-linked Ubiquitination and Lewy Body-like Inclusions. J Cell Physiol. 2020; 235(10):7309-7320.
• Smith WW, Liu Z, Liang Y, Masuda N,Dawson TM, Martin LJ, Moran TH, Lee MK, Borchelt, DR and Ross CA.  Synphilin-1 attenuates neuronal degeneration in the A53T alpha-synuclein transgenic mouse model. Hum Mol Genet. 2010, 19;2087.
• Ma C, Wang X,  Smith WW, Liu Z. VPS35 protects against TMEM230 mutation-induced progressive locomotor deficits in drosophila. Neuroscience Bulletin. 2022; 38:652-656.
• Y Huang, H Huang, L Zhou, J Li, X Chen, J Thomas, X He, W Guo, Y Zeng, B Low, F Liang, J Zeng, CA. Ross, E Tan, Smith WW, and Z Pei. Mutant D620N and VPS35 induces motor dysfunction and impairs DAT-mediated dopamine recycling pathway.  Hum Mol Genet. 2022;31(22):3886-3896.

Metabolic pathways and obesity

We pioneered reporting that expression of synphlin-1 in neurons causes hyperphagia and obesity. We have elucidated the AMPK signaling pathway meditating the synphilin-1-induced positive energy balance. We generated the novel genetic obesity models including human transgenic synphlin-1 mouse and Drosophila models for pathogenesis, biomarker identification and therapeutic studies.

• Li T, J Liu, G Guo, B Ning, X Li, G Zhu, D Yang, TH. Moran and *Smith WW. Synphilin-1 interacts with AMPK, and increases AMPK phosphorylation. Int J Mol Sci. 2020 Jun 18;21(12):4352. 
• Liu J, X Wang, R Ma, T Li, G, Guo, B Ning, TH Moran and Smith WW. AMPK signaling mediates synphilin-1-induced hyperphagia and obesity in Drosophila. J. Cell Sci. 2021, 134(3):jcs247742.
• T Li, J Liu, and WW Smith. Synphilin-1 binds ATP and regulates intracellular energy status. PLOSONE 2014: 9(12):e115233. 
• Smith WW, Li T, Thomas J, Moran TH. From fat fruitfly to human obesity. Physiology and  Behavior. 2014: pii: S0031-9384(14)00034-1. 

Neuroimaging and biomarker identification

Developing biomarkers for early diagnostics and treatment evaluation is critical for disease prognosis. We have used the new Magnetic Resonance Imaging (MRI) techniques combined functional and pathological assessments to measure brain dynamic changes in mouse models of PD, AD and dementia to identify non-invasive biomarker (s) for disease process and treatment evaluation. These studies are translational as the MRI methods we developed can also be applied to humans. Thus, the imaging biomarkers identified by us will be most likely used in for early diagnosis and treatment evaluation in PD clinic. 

Exploring novel treatment strategies

• Small Molecule Compounds: Using computer-aided drug design (CADD) and biological screens, we have developed several lines of therapeutic studies. We have identified the potential novel compounds that protect against alpha-synuclein and LRRK2 toxicity. We recently identified series of LRRK2 GTP binding inhibitors and kinase inhibitors that can reduce LRRK2 kinase activity and protect against mutant LRRK2-induece pathology. In a collaboration study, we have also identified novel compounds that have anti-cancer effects.
• Gene therapy: We have developed the novel genetic circuits and AAV-mediated approaches to either up- or down-regulate the therapeutic targets in the pathological pathways to attenuate neurodegeneration and neuroinflammation thereby suppressing the pathology and phenotypes of PD, AD, HD and dementia.
• Digital and Artificial Intelligence(AI)-aid Treatment: We have collaborated with experts in the AI field to optimize the pathological and pathophysiological assessments, to guide the biomarker identification and novel treatment development and validation.