Speaker Profile

Executive Summary：
Dr. Wei-Li Wu is an associate professor in the Department of Physiology at the College of Medicine, National Cheng Kung University. Dr. Wu received his Ph.D. degree in neuroscience with Dr. Chih-Cheng Chen as advisor at the Academia Sinica. In the Ph.D. training, Dr. Wu profiled the alternations of emotion-related behaviors in a mouse model with sensory deficits. After completing the doctoral degree, Dr. Wu joined the late Prof. Paul Patterson laboratory at Caltech as a postdoctoral scholar in neuroimmunology from 2012 to 2014. In Patterson laboratory, Dr. Wu focused on the gene x environment interactions in a preclinical mouse model of autism spectrum disorder (ASD) and schizophrenia, maternal immune activation. In 2014, Dr. Wu joined Prof. Sarkis Mazmanian laboratory at Caltech to carry on his works from the Patterson lab and to explore a fascinating topic: understanding how gut microbiota mediate mental homeostasis and disorder. In 2018, Dr. Wu set up his laboratory at National Cheng Kung University and continuously worked to unravel the neural mechanism by which gut microbiota impact brain circuits and host behaviors. Dr. Wu interrogated the microbiota-based neural circuits underlying the various innate behaviors using microbiome-manipulated mice.

Lecture Abstract：
Locomotor activity is an innate behavior that can be triggered by gut-motivated conditions, such as appetite and metabolic condition. Various nutrient-sensing receptors distributed in the vagal terminal in the gut are crucial for signal transduction from the gut to the brain. The levels of gut hormones are closely associated with the colonization status of the gut microbiota, suggesting a complicated interaction among gut bacteria, gut hormones, and the brain. However, the detailed mechanism underlying gut microbiota-mediated endocrine signaling in the modulation of locomotion is still unclear. Herein, we show that broad-spectrum antibiotic cocktail (ABX)-treated mice displayed hypolocomotion and elevated levels of the gut hormone glucagon-like peptide-1 (GLP-1). Blockade of the GLP-1 receptor and subdiaphragmatic vagal transmission rescued the deficient locomotor phenotype in ABX-treated mice. Activation of the GLP-1 receptor and vagal projecting brain regions led to hypolocomotion. Finally, selective antibiotic treatment dramatically increased serum GLP-1 levels and decreased locomotion. Colonizing Lactobacillus reuteri and Bacteroides thetaiotaomicron in microbiota-deficient mice suppressed GLP-1 levels and restored the hypolocomotor phenotype. Our findings identify a mechanism by which specific gut microbes mediate host motor behavior via the enteroendocrine and vagal-dependent neural pathways.

Executive Summary：
Dr. Lorraine Kalia is a clinician-scientist at the University of Toronto whose clinical practice and research program focus on Parkinson’s disease. She received her MD/PhD and neurology residency training at the University of Toronto. She conducted a postdoctoral research fellowship at Massachusetts General Hospital and a movement disorders fellowship at Toronto Western Hospital. Currently, she is an associate professor in the Division of Neurology at the University of Toronto and a senior scientist in the Krembil Brain Institute at University Health Network. She is also a movement disorders neurologist in the Edmond J. Safra Program in Parkinson’s Disease and
Morton and Gloria Shulman Movement Disorders Centre at Toronto Western Hospital. She holds the Wolfond-Krembil Chair in Parkinson’s Disease Research.

Her research program aims to understand the key molecular mechanisms responsible for neurodegeneration in Parkinson’s disease and to identify therapeutic agents that can modulate these molecular mediators of neurodegeneration. Her group uses a comprehensive approach involving molecular biology and biochemical techniques, cellular models, and in vivo invertebrate and vertebrate systems. Dr. Kalia is the treasurer of the Canadian Movement Disorders Society and co-chair of the Scientific Issues Committee and the Basic Science Special Interest Group of the International Parkinson and Movement Disorder Society. She is co-editor-in-chief of the Journal of Parkinson’s Disease.

Lecture Abstract：
Protein dyshomeostasis, or proteostasis, is a hallmark of Parkinson’s disease, characterized by the accumulation of alpha-synuclein into toxic oligomers and fibrils that contribute to neurodegeneration. A high-throughput, proteome-wide peptide screening approach was employed to identify inhibitors of protein-protein interactions that can reduce alpha-synuclein oligomer levels and their associated cytotoxicity. A specific peptide inhibitor was identified that disrupts the direct interaction between alpha-synuclein and charged multivesicular body protein 2B (CHMP2B), a key component of the endosomal sorting complex required for transport-III (ESCRT-III). The ESCRT machinery is essential for the endolysosomal system, which manages intracellular trafficking and degradation. Findings indicate that alpha-synuclein inhibits endolysosomal activity through its interaction with CHMP2B, consequently preventing its own degradation. Notably, the peptide inhibitor was found to restore endolysosomal function, leading to decreased alpha-synuclein levels across various models, including human iPSC-derived neurons with pathogenic alpha-synuclein mutations. Additionally, the peptide demonstrated protective effects on dopaminergic neurons against alpha-synuclein-induced degeneration in both C. elegans and preclinical rodent models of Parkinson’s disease. These results suggest that targeting the interaction between alpha-synuclein and CHMP2B with this peptide inhibitor may offer a promising strategy to correct protein dyshomeostasis in Parkinson’s disease.

Executive Summary：
Prof. Tiago Outeiro graduated in Biochemistry at the University of Porto and was an Erasmus student at the University of Leeds in the UK. Prof. Outeiro did his PhD thesis at the Whitehead Institute for Biomedical research – MIT and worked at FoldRx Pharmaceuticals as a Research Scientist and Consultant. Prof. Outeiro was a Postdoctoral Research Fellow in the Department of Neurology of the Massachusetts General Hospital – Harvard Medical School where he focused on the study of Neurodegenerative disorders such as Parkinson’s and Alzheimer’s disease. Prof. Outeiro directed the Cell and Molecular Neuroscience Unit at IMM, Lisbon, from 2007 to 2014, and is currently Full Professor and the Director of the Department of Experimental Neurodegeneration at the University Medical Center Goettingen, in Germany. Prof. Outeiro holds a joint Professor position at Newcastle University in the UK, and is an invited Professor at the University of the Algarve. Prof. Outeiro has authored >300 research articles in international journals and participates in various international boards and in collaborative projects with the aim of identifying the molecular basis of neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease. He has been awarded multiple prizes and grants in Germany, from the European Union, and from other international funding agencies.

Lecture Abstract：
The accumulation of proteinaceous inclusions rich in alpha-synuclein in the brain is a common feature in Parkinson's disease (PD), and dementia with Lewy bodies (DLB). Interestingly, these inclusions are enriched not only in α-synuclein (aSyn), but also in lipid species, organelles, membranes, and even nucleic acids. Furthermore, several genetic risk factors for PD are mutations in genes involved in lipid metabolism, such as GBA1, VSP35, or PINK1. Thus, it is not surprising that mechanisms that have been implicated in PD, such as inflammation, altered intracellular and vesicular trafficking, mitochondrial dysfunction, and alterations in the protein degradation systems, may be also directly or indirectly connected through lipid homeostasis. Therefore, lipid biology may constitute an important driver of PD, and requires renovated attention. Lipids may bear implication in the accumulation of aSyn and in the spreading of aSyn pathology, in mitochondrial dysfunction, and in ER stress. Together, this suggests we should broaden the view of PD not only as a proteinopathy but also as a lipidopathy.