The Center for Parkinson’s Disease Neurobiology, part of The Friedman Brain Institute, integrates basic and clinical PD research at Mount Sinai and builds interdepartmental and core facility collaborations. We employ multi-disciplinary approaches, such as single-cell transcriptomics, spatial transcriptomics, proteomics, molecular and neural circuit, genetic mouse models, biochemistry, structure biology, human stem cell-induced 2D and 3D models (organoids), and small molecule screening for therapeutic development.

Profiling and Elucidating Molecular and Cellular Mechanism of Neuronal Vulnerability/Resilience: The goal of this study is to characterize cell diversity at PD-associated brain region, elucidate molecular mechanism for vulnerability and resilience of dopaminergic (DA) neurons, and identify neuroprotective strategies to treat PD. We use three biological systems: human postmortem tissue, genetic mouse models, and induced human DA neuron cultures in this study. We expect to identify key genetic and network factors, which, when manipulated, will enable us to develop strategies to overcome the vulnerability or promote the resilience of DA neurons and to treat PD. This study is supported by Parkinson’s Foundation Research Center and led by Zhenyu Yue, PhD. Other faculty members involved with the research include Bin Zhang, PhD, Nan Yang, PhD, John Crary, MD, PhD, and Joel Blanchard, PhD.

Molecular and Cellular Basis of the Gut-Brain Axis: Many PD patients develop constipation and gastrointestinal illness prior to the manifestation of motor symptoms. An increased incidence of PD in patients with inflammatory bowel disease (IBD), a chronic disease of the gut, has also been reported worldwide. With the finding of -synuclein Lewy bodies in peripheral tissues (e.g., gut) of PD patients, there is a growing appreciation for the hypothesis of gut-brain axis and chronic inflammation in the disease onset and progression for PD. The link between intestinal inflammation and PD is also enforced by elevated markers of intestinal inflammation, such as fecal calprotectin, and pro-inflammatory gut microbiota composition observed in PD patients. Drs. Peter and Yue have recently reported the link of leucine-rich repeat kinase 2 (LRRK2) variants (e.g., N2081D) to the increased risk of both IBD and PD. Our study and others demonstrate a role of LRRK2-mediated signaling in promoting both PD and IBD. We are investigating human intestinal samples of PD and IBD, novel genetic LRRK2 models, and new -synuclein gut-brain transmission models. Our study is expected to determine subtypes of PD that are associated with prodromal gut chronic inflammation, identify molecular and cellular mechanism underlying gut-brain axis of PD, and develop biomarkers and novel therapeutics for PD. This research is supported by the National Institutes of Health/National Institute of Neurological Disorders and Stroke (P20, Exploratory Program for Parkinson’s Disease Research) and MJ Fox Foundation, and led by Zhenyu Yue, PhD, Rachel Saunders-Pullman, MD, MPH, and Inga Peter, PhD. Other faculty members are Bin Zhang, PhD, Wenfei Han, PhD, DDS, Ivan de Araujo, PhD, and Saurabh Mehandru, MD.

LRRK2 pathogenic pathways and therapeutic development: Missense mutations in the LRRK2 gene are the most common genetic cause for Parkinson’s disease (PD) and some sporadic PD cases. LRRK2 has now emerged as a major target of PD therapeutics. Multiple lines of evidence suggest a “gain-of-function” hypothesis that LRRK2 pathogenic mutations cause increased kinase activity associated with neurotoxicity. While several putative LRRK2 substrates, including small Rab GTPase proteins, have been reported, their functional relevance to LRRK2 pathogenic pathways remains poorly understood. LRRK2 may function in vesicle trafficking, autophagy-lysosome pathways, cytoskeletal dynamics, protein translation, mitochondria dynamics, inflammatory response, and ciliogenesis. We will dissect molecular and cellular mechanisms underlying LRRK2-mediated pathogenesis by using multiple LRRK2 mutant mouse models and human induced neurons. Our study is expected to identify molecular biomarkers and novel therapeutic targets for PD. The faculty members involved in the research are Zhenyu Yue, PhD, Inga Peter, PhD, Deanna L. Benson, PhD, George Huntley, PhD, Susan Bressman, MD, and Rachel Pullman-Saunders, MD, MPH.