2023 Grand Challenges in Parkinson’s Disease

Nicole Calakos, M.D., Ph.D., is a physician-scientist who cares for patients with movement disorders and maintains an active laboratory research program. Dr. Calakos is the Lincoln Financial Group Professor of Neurology and Neurobiology and Chief of the Movement Disorders section in Neurology at Duke University Medical Center. Her laboratory studies how synaptic plasticity generates learning and adaptive behavior; and how its disruption causes diseases of the basal ganglia circuitry. The Calakos Lab is widely recognized for its contributions to understanding habit formation, compulsive behavior and dystonia and for the generation of new methodologies to study basal ganglia physiology.

Dr. Calakos received her bachelor’s degree from the University of California at Berkeley, her M.D. and Ph.D. degrees from Stanford University, and residency training in neurology at the University of California at San Francisco.

Dr. Calakos’ contributions have been recognized through a number of awards, leadership and service opportunities. She is a member of the National Academy of Medicine, fellow of the American Association for the Advancement of Sciences, and 2023 recipient of the ASCI Korsmeyer award. Dr. Calakos advocates for basic and translational neuroscience through these organizations and activities that have included: the Board of Directors for the American Neurological Association, governance committee for the Duke University Institute for Brain Sciences and scientific advisory boards for disease foundations.

Dr. Rui Chang received his B.S. in Biological Sciences and Biotechnology from Tsinghua University, China, in 2005. He then studied sensory transduction with Emily Liman and earned his Ph.D. in Neuroscience at the University of Southern California in 2011. He completed his postdoctoral training with Stephen Liberles at Harvard Medical School, where he investigated how body sensory cues are monitored by the brain through the vagus nerve, and how these internal signals regulate whole body physiology. He joined both the Department of Neuroscience and the Department of Cellular and Molecular Physiology at Yale University School of Medicine in January 2018. The Chang lab uses state-of-the-art molecular, genetic, and imaging approaches including single-cell gene expression profiling, virus-based anatomical mapping, in vivo imaging, optogenetics, and chemogenetics to reveal the physiological functions of diverse organ-to-brain circuits. The goal is to better understand the important body-brain interface, and to develop novel neuronal-based therapeutic strategies for disease intervention.

Dr. Hong-yuan Chu received his Ph.D. in pharmacology from Shanghai Institute of Materia Medica. He then completed postdoctoral training at the National Institute of Mental Health and Northwestern University. In 2019, he joined Van Andel Institute’s Department of Neurodegenerative Science as an assistant professor. Dr. Chu serves as a reviewer for eLife, Journal Parkinson’s Disease, the Frontiers journals, and others. He is the recipient of several awards, including the prestigious 2020 BBRF Young Investigator Award.

Dr. Mark R. Cookson is a cell biologist whose current research interests include the effects of mutations in the genes associated with neurodegeneration at the cellular and molecular level. His laboratory efforts are directed at finding the underlying pathways that lead to Parkinson’s disease and related disorders. Dr. Cookson received both his B.Sc. and Ph.D. degrees from the University of Salford, UK in 1991 and 1995, respectively. His postdoctoral studies included time spent at the Medical Research Council laboratories and at the University of Newcastle, Newcastle, UK. He joined the Mayo Clinic, Jacksonville, Florida, as an Assistant Professor in 2000 and moved to the NIA in February 2002. Within the Laboratory of Neurogenetics, Dr. Cookson’s group works on the effects of mutations associated with Parkinson’s disease on protein function.

Dr. Ferguson’s laboratory has made significant discoveries relating to two crucial areas of research: fundamental mechanisms governing lysosome function and the contributions of lysosome dysfunction to neurodegenerative diseases. Specifically, their research has provided valuable insights into the control of signaling protein abundance at lysosomes, including the dynamic shuttling of the MiT-TFE family of transcription factors between lysosomes and the nucleus. This process helps match lysosome function to changing cellular demands. Additionally, the lab has uncovered the regulation of Rag GTPases by folliculin, a tumor suppressor, and mechanisms of mTORC1 activation at lysosomes. The lab has furthermore defined a novel C9orf72-containing protein complex that controls lysosome responses to amino acid availability. These findings have revealed how lysosomes integrate various inputs concerning lysosome homeostasis and nutrient availability, generating essential signals to communicate this information throughout the cell. In addition to signaling from lysosomes, Dr. Ferguson has also identified regulators of the lysosome transport in neuronal axons with neurodegenerative disease implications. Most recently, the Ferguson laboratory identified a critical role for LRRK2 in controlling lysosome degradative activity in macrophages and microglia. Notably, they found that excess LRRK2 activity, associated with the G2019S familial Parkinson’s disease mutation, suppresses lysosome degradative function. To deepen the understanding of both fundamental cell biology and the impact of LRRK2 dysregulation in Parkinson’s disease, ongoing research focuses on defining the mechanisms of LRRK2 activation and the specific LRRK2 targets that mediate its functions at lysosomes in neurons and glia.

Sonia obtained an MA in Neuroscience at the University of Cambridge, a degree in Medicine at the University of Oxford and completed a PhD in Neuroscience at UCL Institute of Neurology. She undertook Wellcome Career Development Fellowship, establishing her own laboratory in 2014 at UCL QS Institute of Neurology, and was seconded to The Francis Crick Institute in 2017. In 2020 she was awarded an MRC Senior Clinical Fellowship and promoted to Professor of Neurology in 2021.

Her research program focusses on understanding the molecular and cellular mechanisms that cause neurodegenerative diseases, specifically familial forms of Parkinson’s disease. Her laboratory has adopted an interdisciplinary approach, combining single molecule biophysics with human stem cell systems to understand how and why proteins misfold in human cells, and then defining the organellar and cellular consequences of protein aggregation. Funded by the global initiative, Aligning Science Across Parkinson’s, her group is utilising a range of single cell, single molecule and spatial technologies to generate a detailed molecular and cellular map of the human Parkinson’s brain. Through an MRC Multiscale Program award, her group models subtypes of Parkinson’s across different scales and modalities, integrating cellular, computational, and clinical neuroscience to understand progression in Parkinson’s.

Anastasia (Stacy) Henry leads a team of scientists within the Pathway Biology group at Denali Therapeutics.  Her lab is focused on understanding the mechanisms by which disease-associated proteins affect lysosomal function and ultimately contribute to pathogenesis, enabling the development of novel therapeutic approaches to treat Parkinson’s disease and neuronopathic lysosomal storage disorders.  She leads biology efforts to support the LRRK2 kinase inhibitor programs at Denali and to explore the role of lysosomal function in neurodegeneration more broadly. Dr. Henry received her Ph.D. from the University of California, San Francisco in the lab of Mark von Zastrow and her postdoctoral training in the neuroscience department at Pfizer in the lab of Warren Hirst.

Erika L. F. Holzbaur is the William Maul Measey Professor of Physiology at the University of Pennsylvania Perelman School of Medicine. She received her B.S. with High Honors in Chemistry and History from the College of William and Mary and her Ph.D. in Biochemistry from Penn State. Holzbaur joined the faculty at Penn in 1992, where she is now holds an endowed professorship in the Department of Physiology. The Holzbaur lab studies the dynamics of organelle trafficking in neurons. Organelles including mitochondria, autophagosomes, and lysosomes are actively transported over distances of a meter or more along the axons and dendrites of neurons; defects in this trafficking are causative for both neurodevelopmental and neurodegenerative disease. The lab also investigates cellular mechanisms required to maintain neuronal homeostasis, focusing on the dynamics of autophagy and mitophagy. Defects in these pathways lead to the accumulation of dysfunctional organelles and aggregated proteins, and are implicated in both Parkinson’s disease and ALS. Dr. Holzbaur has received a Porter Fellowship, the NINDS Javits Award, the Stanley N. Cohen Biomedical Research Award, the Jane M. Glick Graduate Student Teaching Award, the Sandra K. Masur Senior Leadership Award, and is a Lifetime Fellow and current President of the American Society for Cell Biology. More than 40 postdocs and students have trained in her lab, many now running research labs at top universities in the US and internationally.

George W. Huntley received his B.A. in Physiology from UC San Diego and his Ph.D. in Neuroscience at UC Irvine working with Edward G. Jones on the structural and functional organization of motor representations in monkey motor cortex. His postdoctoral training with Dr. John Morrison focused on defining GluA subunit distribution at identified synapses in primate cerebral cortex. His early work in his own laboratory explored mechanisms of circuit plasticity of motor representations in motor cortex and the role of somatosensory experience in shaping development of motor representations, work for which he was awarded the Cajal Club’s “Cortical Explorer Prize.” Subsequent efforts focused on defining how the cadherin family of cell adhesion molecules and extracellular proteolysis proactively shape developing and mature circuits in health and disease. Recent efforts, with his long-time collaborator Deanna Benson, have focused on understanding the basis of early-appearing cognitive and psychiatric-like non-motor symptoms of Parkinson’s, interrogating mouse models behaviorally, anatomically, electrophysiologically and molecularly to infer how risk-gene mutations co-opt circuit structure and function. He is currently Professor of Neuroscience at Mount Sinai and directs the Neuroscience Ph.D. graduate training program.

Hilal Lashuel is an associate professor and the director of the Laboratory of Molecular and Chemical Biology of Neurodegeneration at École Polytechnique Fédérale de Lausanne (EPFL) in Switzerland. Research in the Lashuel laboratory focuses on applying chemical biology approaches to elucidate the mechanisms of protein misfolding and aggregation and their contribution to neurodegenerative diseases with ultimate goal of developing novel therapies and diagnostics for early intervention, and monitoring disease progression.

Dr. Lashuel received his B.Sc. degree in chemistry from Brooklyn College (1994) and completed his doctoral studies at Texas A&M University and the Scripps Research Institute (2000). He joined Harvard Medical School and the Brigham and Women’s Hospital (2001) as a research fellow and was later promoted to an instructor in neurology before joining the EPFL in 2005. In addition to his appointment at the EPFL, Dr. Lashuel served as the Executive Director of Qatar Biomedical Research, a member of the Board of Trustees for the Qatar Biobank and Qatar Genome Project from 2014-2016, and currently serves as the research, development and innovation advisor to the chairperson of Qatar Foundation. He is also founder and CSO of ND BioSciences SA a biotech company focusing on developing novel diagnostics and therapies to treat neurodegenerative diseases.

Dr. Virginia M.-Y. Lee studied music at the Royal Academy of Music in London (1962-1964) and received her Ph.D. in Biochemistry from the University of California at San Francisco in 1973. She joined the Department of Pathology and Laboratory Medicine at the Perelman School of Medicine in 1981 and rose to become Professor of Pathology & Laboratory Medicine in 1989. Dr. Lee identified tau, alpha-synuclein and TDP-43 as disease proteins that form unique inclusions in Alzheimer’s, Parkinson’s and frontotemporal degeneration/Lou Gehrig’s disease, respectively, and has advanced understanding of their roles in these disorders. Dr. Lee’s h-index is 146 and she is listed among the 10 most highly cited AD researchers from 1985-2008 and among the top 400 most highly influential biomedical researchers from 1996-2011. She has been ranked 2 among Top Female Scientists for 2022 by Research.com. Dr. Lee is the recipient of many honors and awards including the Lifetime Achievement Award in Alzheimer’s Disease Research, Robert A. Pritzker Award for Leadership in Parkinson’s Disease Research from the Michael J. Fox Foundation, and the Breakthrough Prize in Life Sciences.

Alexandra Nelson, M.D., Ph.D., is the Richard and Shirley Cahill Endowed Chair in Parkinson’s Disease Research, and Director of the Physician-Scientist Career Development Program at UC San Francisco. Dr Nelson received her M.D./Ph.D. training at UC San Diego, where she studied cellular and circuit mechanisms of cerebellar motor learning. She completed her Neurology residency and postdoctoral training in basal ganglia physiology at UC San Francisco, joining the faculty in 2014. In the lab, her research group investigates the cellular and circuit basis of movement disorders, using electrophysiology, optogenetics, and other optical methods in mouse models of disease. In the clinic, she focuses on the care of patients with neurodegenerative movement disorders, including Huntington’s Disease and Spinocerebellar Ataxias.

A static cell is a dead cell. A broad interest in the Roy lab is to explore movement in neurons — mechanisms that convey, deposit and retain cargoes in axons, dendrites and synapses. A related interest is to manipulate trafficking-pathways for therapeutics in neurodegenerative diseases (particularly gene- and CRISPR- based therapies). Relevant to this meeting, the lab is interested in the physiologic role of alpha-synuclein at synapses, and early pathophysiologic transitions that ultimately lead to Parkinson’s disease and related disorders.

Dr. Sharma’s lab studies neurodegenerative diseases, using molecular-cellular techniques, patient-derived induced neurons, as well as mouse genetic models. He studied microbiology for his undergraduate degree. During his Ph.D. thesis with Dr. Gergely Lukacs, he trained as a molecular cell biologist, while studying misfolding and quality-control of the cystic fibrosis protein CFTR. He applied this training to neuroscience during his postdoctoral training with Dr. Tom Südhof, and acquired mouse genetics skills, in order to study animal models of human neurodegenerative diseases (Burré et al., 2010; Sharma et al., 2011). As an Assistant Professor of Neuroscience at Weill Cornell Medicine, Dr. Sharma’s lab studies neurodegenerative disorders at the molecular-cellular level, including their pharmacological correction-strategies (Naseri et al. 2020; Xie et al. 2022), frequently in collaboration with Dr. Jacqueline Burré’s lab.

Dr. Ellen Sidransky is the Branch Chief of the Medical Genetics Branch and is a pediatrician and geneticist in the National Human Genome Research Institute at National Institutes of Health (NIH). Dr. Sidransky received her B.A. from Brandeis University and her M.D. from Tulane University. She trained in pediatrics at Northwestern University, and in Clinical Genetics at the NIH. Dr. Sidransky has been a tenured NIH investigator and Section Chief since 2000. Her research interests include both clinical and basic aspects of Gaucher disease and Parkinson disease, studies of genotype/phenotype correlation and genetic modifiers, insights from mouse models, and novel treatment strategies. She played a lead role in establishing the association between glucocerebrosidase and parkinsonism. The author of over 200 publications, she continues to focus on the complexity encountered in “simple” Mendelian disorders, the role of lysosomal pathways in parkinsonism, and the development of small molecule chaperone therapy for Gaucher disease and for parkinsonism. She is the recipient of the 2019 Jay Van Andel Award for Outstanding Achievements in Parkinson’s Disease Research, the 2019 U.S. Public Health Service Meritorious Service Medal and the 2021 WORLDSymposium Roscoe O. Brady Award for Innovation and Accomplishment.

Dr. Volpicelli-Daley earned her B.A. in Math and English Literature in college. Her Ph.D. in Neuroscience was earned at Emory University in the lab of Allan Levey, M.D., Ph.D. expert in Alzheimer’s disease and dementias. She also trained in cell biology at Yale University and neurodegenerative disease at the University of Pennsylvania. Dr. Volpicelli-Daley is currently associate professor with tenure at the University of Alabama at Birmingham. Her lab focuses on the how pathologic aggregates of alpha-synuclein contribute to motor and cognitive symptoms in Parkinson’s disease and Lewy body dementias. She is director of a Graduate Neuroanatomy Course and Director of an M.D./Ph.D. course about research in basic sciences. She was awarded the UAB Graduate Dean’s Excellence in Mentorship Award and Outstanding Roadmap Scholars Research Mentor Award.

Dr. Amanda Woerman received her B.A. in botany/microbiology and politics and government from Ohio Wesleyan University in 2008, and her Ph.D. in molecular medicine from The George Washington University in 2013. In July 2013, Dr. Woerman joined Dr. Stanley Prusiner’s laboratory at UCSF as a postdoctoral fellow, where she developed cellular assays for characterizing tau and alpha-synuclein prion strains in neurodegenerative disease. Dr. Woerman joined the faculty at UMass Amherst as an assistant professor in September 2019, where her lab is focused on using strain biology to develop novel diagnostics and therapeutics for neurodegenerative diseases.

Yang Yang’s research interest is assembling and accumulation mechanisms of various amyloids in Neurodegenerative diseases. Dr. Yang completed her Ph.D. in Biochemistry and Molecular biology at the Institute of Biophysics (IBP), Chinese Academy of Sciences in 2017. Then she worked as a research associate in the laboratory of Dr. Zihe Rao focusing on the research of GPCR and Gi-protein complex. Yang started her postdoctoral training in Dr. Sjors Scheres’ laboratory at the Medical Research Council, Laboratory of Molecular Biology to determine the structures of amyloid filaments. Yang explored and characterized the cryo-EM structures of amyloid-β (Aβ) filaments from human brains with Alzheimer’s disease, and α-synuclein filaments from Parkinson’s disease and dementia with Lewy bodies.