Smeyne Research
Contact
- Professor and Chair, Department of Neuroscience
- Director, Jefferson Comprehensive Parkinson's Disease and Movement Disorder Center
- Vickie & Jack Farber Institute for Neuroscience
900 Walnut Street
4th Floor
Philadelphia, PA 19107
The Smeyne laboratory investigates why some individuals develop Parkinson's disease while others remain resilient despite genetic, infectious, inflammatory, or toxic exposures. The program integrates neuroimmunology, neurovirology, genetics, environmental neuroscience, and exercise biology to define mechanisms that initiate or accelerate dopaminergic neurodegeneration and to identify interventions that protect vulnerable neural circuits. Current work emphasizes peripheral-to-central immune signaling, immune aging, multi-hit gene-environment interactions, alpha-synuclein biology, and exercise-induced neural plasticity. His research program is embedded in the Vickie & Jack Farber Institute for Neuroscience and the Jefferson Comprehensive Parkinson's Center, enabling interaction among basic scientists, neurologists, neurosurgeons, rehabilitation specialists, immunologists, virologists, and translational investigators.
Research Strategy
A unified program organized around susceptibility, triggers, progression, protection, and translation
The Smeyne laboratory uses complementary mouse models, viral and inflammatory challenges, environmental toxicants, cell-specific genetic approaches, immunophenotyping, transcriptomics, proteomics, neurochemical analysis, quantitative neuropathology, and behavioral assays. The central premise is that Parkinson's disease emerges from interactions among host genotype, biological age, immune state, environmental history, and activity-dependent resilience rather than from a single isolated insult.
Research Programs
Peripheral Immunity, Immune Aging, and Brain Vulnerability
A major focus of the laboratory is defining how immune responses outside the brain influence microglial activation and dopamine-neuron survival. This program grew from studies showing that non-neurotropic H1N1 influenza can produce persistent microglial activation in the substantia nigra and hippocampus despite the absence of detectable virus in the central nervous system. The findings shifted attention from direct brain infection to systemic immune-to-brain communication as a potential contributor to neurodegenerative risk.
LRRK2 provides a mechanistic bridge between familial Parkinson's disease and immune signaling. In bone-marrow chimera studies, replacing mutant LRRK2-expressing T and B lymphocytes with wild-type immune cells reduced inflammation and rescued substantia nigra dopamine-neuron loss. Conversely, mutant LRRK2 confined to lymphocytes was sufficient to confer vulnerability in a genetically wild-type brain. Neutralization of excess peripheral IL-6 prevented neuronal loss, identifying a tractable circulating mediator.
The current 2026 Aligining Science Across Parkinson’s/Michael J. Fox Foundation collaborative project with scientists from Indiana University, Mayo Clinic, and Tulane University examines immune cell exhaustion and biological immune aging in people with Parkinson's disease, individuals at elevated risk, and unaffected controls, together with mechanistic preclinical models. The project is designed to identify blood-based signatures of immune dysfunction, explain heterogeneity in onset and progression, and nominate immune-directed prevention or treatment strategies for biologically defined patient groups.
Exercise-Induced Neuroprotection and Circuit Plasticity
Exercise is both a clinically actionable intervention and a biological probe of resilience. The Smeyne laboratory established that sustained voluntary exercise or environmental enrichment can protect substantia nigra dopamine neurons in toxin-based models, defined exposure duration and intensity requirements in mice, and demonstrated that HIF-1alpha signaling is necessary for exercise-induced neuroprotection.
The current program moves beyond cell survival to delineating the mechanisms underlining exercise-induced neurprotection. Theseinclude alterations in vascular development, mitochondrial function, oxidative defense, neurotrophic signaling and inflammation, synaptic remodeling, and behavior.
Ongoing priorities include identifying molecular and epigenetic signatures of effective exercise, determining how exercise dose and timing influence benefit, and defining biomarkers that can stratify responders. The long-term goal is to use exercise biology to guide both optimized rehabilitation and development of pharmacologic or behavioral mimetics.
This project involves collaborative work with the Calabresi lab at Università Cattolica, Policlinico Gemelli IRCCS in Rome, the Hassin-Baer lab at Sheba Medical Center in Israel and the Bernstein lab at Rutgers University.
Viral Infection and Long-Term Neuroinflammatory Priming
The Smeyne laboratory studies both neurotropic and non-neurotropic viruses to distinguish direct viral injury from persistent host-mediated effects. Earlier work with H5N1 demonstrated neural-route invasion and Parkinsonian neuropathology, while H1N1 studies showed durable microglial activation without brain infection. This comparative approach established that different pathogens can converge on neurodegenerative pathways through distinct mechanisms.
SARS-CoV-2 studies extended this framework to a contemporary human pathogen. In preclinical models, infection with WA-1/2020 or Omicron B1.1.529 sensitized wild-type and G2019S LRRK2 mice to a subsequently administered subtoxic dose of MPTP, but not paraquat. The work also demonstrated strain-, genotype-, and vaccination-dependent differences in inflammatory and neuropathological outcomes, reinforcing the importance of exposure history and host background.
The Smeyne lab, in collaboration with a numebr of labs, has also examined the role of infection. Collaborative studies with the Tjalkens lab (Colorado State University, Barrow Neurologic Institute) provide a complementary model of direct viral encephalitis. Following nonlethal infection with western equine encephalitis virus (WEEV), mice developed selective and persistent loss of substantia nigra dopaminergic neurons, sustained microglial and astrocytic activation, and widespread alpha-synuclein aggregation. Mechanistic follow-up demonstrated that astrocyte NF-kappaB signaling and complement C3 contribute to this pathology: astrocyte-specific disruption of NF-kappaB signaling reduced gliosis, alpha-synuclein aggregation, and dopamine-neuron loss. Together, these studies identify glial inflammatory signaling as a mechanistic link between encephalitic infection and postencephalitic parkinsonism and suggest a potential point for therapeutic intervention. In another collaborative study (Snyder lab at TJU) we examined the role of neonatal murine cytomegalovirus that showed that an early-life infection can produce persistent, inflammatory microglial states and delayed neuronal loss in the retina and cortex long after acute viral control. These collaborative studies broaden the research program in the Smeyne lab beyond adult respiratory infection and tests the concept that early immune events can leave durable neurobiological consequences.
Gene-Environment and Multi-Hit Models of Parkinsonian Neurodegeneration
Most Parkinson's disease is likely to reflect combinations of susceptibility factors rather than a single sufficient cause. The laboratory therefore models sequential or concurrent exposures that individually produce limited injury but together cross a threshold for persistent neuroinflammation, synaptic dysfunction, mitochondrial stress, and neuron loss.
Recent manganese-influenza studies illustrate this strategy. In collaboration with the Tjalkens lab (Colorado State University, Barrow Neurologic Institute), mice exposed to manganese followed by adult H1N1 infection increased hippocampal microglial activation and pyknotic neurons, extending earlier findings in the substantia nigra. These experiments address how developmental toxicant exposure can alter the later response to infection and create region-specific vulnerability.
We are also interested in how gene-environment interactions affects the expression of alpha-synuclein. A recent study using the preformed filament model of induced synucleiopathy showed that injection of these misfolded PFFs into the striatum induced inflammatory and nigral pathology in wild-type mice, whereas both fibrillar and nominally wild-type monomeric alpha-synuclein induced pathology in A53T overexpressing alpha-synuclein-expressing mice. The results support the idea that a susceptible alpha-synuclein background can lower the threshold for templating, inflammation, and dopamine-neuron loss.
The laboratory also collaborates to identify endogenous resilience pathways. Recent work in collaboration with the Waldman lab (TJU) examines the role of guanylyl cyclase C (GUCY2C), a membrane receptor activated by guanylin and uroguanylin that generates cyclic GMP, that acts to regulate intestinal fluid and electrolyte balance, epithelial integrity, and barrier function. GUCY2C is also expressed in several brain regions, where its signaling may influence neuronal excitability, appetite, energy balance, and communication between the gut and brain. Recent experimental studies in our labs further suggest that GUCY2C signaling may protect midbrain dopaminergic neurons from toxic injury, raising the possibility that altered GUCY2C activity could affect vulnerability to neurodegenerative disorders such as Parkinson’s disease.
Blood Biomarkers and Mechanism-Based Translation
The Smeyne lab has long-standing interest in identyfing peripheral biomarkers that reveal latent vulnerability before the typical motor symptoms of Parkinson’s disease emerge. Earlier Michael J. Fox Foundation-supported work tested stress-induced GSTpi responses in blood cells as a candidate biomarker. These studies are being extended to examine other proteins in the anti-oxidant pathways including glutathione and glutathione turnover as well as other mitchondrial respiratory proteins.
Additionally, our current immune-aging program extends this translational direction by measuring how human immune cells respond to stress and by seeking signatures that distinguish Parkinson's disease, elevated-risk states, and unaffected aging.
The translational objective is not simply to classify Parkinson's disease as present or absent, but to define biological subtypes that can guide prevention, prognosis, and therapeutic selection. The Jefferson Comprehensive Parkinson's Center provides an environment in which laboratory discoveries can be connected to clinical cohorts, multidisciplinary care, and trial development.