Dopaminergic Circuit Function, Metabolism, and Selective Vulnerability
Six Fellows are investigating how synaptic signaling, axonal architecture, neuromodulation, and bioenergetic stress converge to drive selective vulnerability within dopaminergic circuits in Parkinson’s disease. Their work incorporates human-derived models of dopaminergic neuron subtypes, mechanisms of neurotransmitter release and modulation in basal ganglia circuits, and the impact of metabolic dysfunction on synaptic and circuit-level dopamine dynamics. By linking metabolic demands and molecular pathology to circuit function and behavior, these researchers seek to explain why specific dopaminergic neuron populations are affected by Parkinson’s disease neurodegeneration while other populations remain resilient, and to identify strategies to restore dopamine signaling and motor function.
Sayan Dutta, PhD
Project Title: Dissecting the effects of alpha-synuclein pathology on the selective vulnerability of midbrain dopaminergic neuronal subtypes utilizing spatial single-cell proteomics
Home Team: Gradinaru (Gradinaru Lab)
Host Team: Awatramani (Awatramani Lab)
Institution: California Institute of Technology
Project Summary: Loss of midbrain dopaminergic neurons (mDANs) underlies motor dysfunction in Parkinson’s disease. In patients, neurons in the ventral substantia nigra pars compacta are particularly vulnerable, whereas dorsal neurons are resistant. Basal transcriptomic differences cannot fully explain this selective cell-type vulnerability. This project will explore whether an additional disease-causing factor, such as alpha-synuclein aggregation, is needed for mDANs to exhibit a Parkinson’s disease-like vulnerability trend. This project will test whether alpha-synuclein pathology preferentially induces degeneration of Anxa1⁺ ventral mDANs using AAV-mediated aSyn overexpression in mice. In addition, spatial single-cell proteomics in mouse and Parkinson’s disease patient tissue will be used to define subtype-specific molecular pathways and protein targets mediating vulnerability or resilience.
Janko Kajtez, PhD
Project Title: Recapitulating subtype-specific cell-autonomous human dopaminergic vulnerability in Parkinson’s disease
Home Team: Jakobsson (Kirkeby Lab)
Host Team: Studer (Studer Lab)
Institution: University of Copenhagen
Project Summary: The selective vulnerability of A9 dopaminergic neurons in Parkinson’s disease may arise from their extraordinary bioenergetic demands, driven by large axonal arbors and pacemaking activity. To test this hypothesis in a human context, this project integrates stem cell technology and bioengineering to control axonal length and activity, model Parkinson’s disease-penetrance factors, and assess axonal transport deficits. By combining structural, functional, and molecular analyses, this work aims to define how arbor size and metabolic load intersect with these stressors to trigger A9 degeneration. These insights will provide a foundation for innovative strategies to model and treat Parkinson’s disease.
Christiana Kontaxi, PhD
Project Title: LRRK2 and neurotransmitter release
Home Team: Edwards (Edwards Lab)
Host Team: Awatramani (Bevan Lab)
Institution: University of California, San Francisco
Project Summary: Mutations in the leucine-rich repeat kinase 2 (LRRK2) are a common cause of Parkinson’s disease, but the mechanism remains unknown. Although most research on pathogenesis focuses on dopamine neurons that degenerate in Parkinson’s disease, LRRK2 is highly expressed in spiny projection neurons in the striatum, suggesting the mutations affect basal ganglia circuitry. Previous work recently identified a specific effect of the G2019S LRRK2 Parkinson’s disease mutation on GABA release by striatal neurons. This project will investigate the role of this defect in basal ganglia circuitry and the mechanism by which G2019S LRRK2 impairs release.
Mukesh Kumar, PhD
Project Title: Does pathogenic α-synuclein disrupt lipid droplet–mitochondria coupling in Parkinson’s disease?
Home Team: De Camilli (Ryan Lab)
Host Team: Edwards (Edwards Lab)
Institution: Weill Cornell Medicine
Project Summary: Emerging evidence highlights bioenergetic failure as a central driver of Parkinson’s disease pathology, accompanied by abnormal triglyceride (TG) accumulation in neuronal lipid droplets (LD) in Parkinson’s disease brain. Previous work recently overturned the dogma that the brain and neurons do not carry out beta-oxidation, underpinned by the discovery of mutations in a neuron-specific TG lipase. Notably, alpha-synuclein fibrils readily associate with LDs, suggesting a link between synucleinopathy, TG metabolism, and bioenergetics. This project tests the hypothesis that alpha-synuclein-LD interaction alters TG turnover, thereby compromising beta-oxidation and ATP production to drive synaptic dysfunction. This metabolic bottleneck may contribute to progressive neurodegeneration in Parkinson’s.
Matthew McGregor, PhD
Project Title: How the spatiotemporal dynamics of dopamine transmission shift in Parkinson’s disease to support motor function
Home Team: Edwards (Ford Lab)
Host Team: Surmeier (Ding Lab)
Institution: University of Colorado Anschutz Medical Campus
Project Summary: Limited understanding of dopamine spatial dynamics is a major constraint on treating Parkinson’s disease. While broad regional dynamics have been extensively characterized, how local dynamics are encoded in striatal circuits and how they are altered in Parkinson’s disease remain unclear. This project aims to determine how alpha-synuclein accumulation and progressive dopamine neuron degeneration impact local dopamine dynamics to drive the motor symptoms of Parkinson’s disease. Using 2-photon imaging to map local dopamine dynamics in two Parkinson’s disease models, this work will determine how changes in these dynamics induce impaired behavior. Together, these studies will establish a new paradigm for exploring dopamine dynamics in Parkinson’s disease.
Kathryn Todd, PhD
Project Title: Parsing the diverse neuromodulation of vulnerable versus resistant dopamine axons according to distinct molecular subtype
Home Team: Cragg (Cragg Lab)
Host Team: Awatramani (Dombeck Lab)
Institution: University of Oxford
Project Summary: Dopamine axon function, and therefore striatal output and behavior, is profoundly and diversely shaped by striatal neuromodulators. Crucially, a previously underappreciated heterogeneity of dopamine neurons exists whereby molecularly-distinct dopamine neuron subtypes exhibit differential vulnerability to degeneration in Parkinson’s disease. However, how distinct neuromodulators govern dopamine axon function of these distinct subtypes is not known. This project will fill this knowledge gap using a multi-disciplinary approach and state-of-the-art tools. By characterizing distinct modulatory mechanisms of vulnerable versus resistant dopamine axons, this work can inform the development of targeted and improved strategies to rescue dopamine dysfunction in Parkinson’s disease.
