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Understanding and Manipulating Cellular and Circuit-level Vulnerability to Neurodegeneration in Parkinson’s Disease

Study Rationale:
Many people with Parkinson’s disease develop untreatable cognitive symptoms, including problems with attention, decision-making, and dementia at late stages of the disease, due to changes in a crucial part of the brain, the cerebral cortex. Evidence suggests that aggregation of the protein alpha-synuclein in vulnerable nerve cells interferes with their health and damages the cellular networks required for normal brain function; however, the relationships between alpha-synuclein, vulnerable cells, and network activity are not understood. By identifying and understanding the causes and effects of this damage in brain networks, and affected nerve cells and their connections, we aim to enable therapies that directly target this disorder.

We hypothesize that networks of nerve cells in the cortex of the brain become dysfunctional because of damage caused by pathological deposits of the protein alpha-synuclein in vulnerable cells.

Study Design:
We will assess how alpha-synuclein pathology progressively impairs network function in the brain cortex and identify the features distinguishing vulnerable from resilient cells using innovative technologies, including imaging of activity in the live brain, measurements of attention, profiling of different cell types and their contents, and high-resolution microscopy of neuronal connections. We will integrate these data using advanced computational methods to design and test cell-specific interventions to restore the function of the disrupted networks. This study will reveal mechanisms of cortical network damage in Parkinson’s disease and will identify the types of nerve cells suited for therapeutic intervention.

Impact on Diagnosis/Treatment of Parkinson’s Disease:
Diagnostic biomarkers for Parkinson’s disease can leverage our findings of which types of neurons, their connections, and molecular markers are most affected. For treatment, our work will define novel mechanisms that can directly restore network function by targeting specific types of cortical nerve cells and their connections.

Next Steps for Development:
Given the successful restoration of cortical network functions in our mouse model of Parkinson’s disease, the next steps can include studies in humanized mice and other pre-clinical models to explore and optimize treatment methods that could be adapted for use in the clinic. These can include medications targeted to the types of neurons we here identify as vulnerable in order to modulate their activity, and development of new translational biomarkers.


  • William C. Mobley, MD, PhD

    La Jolla, CA United States

  • Thomas Biederer, PhD

    New Haven, CT United States

  • Elena O. Gracheva, PhD

    New Haven, CT United States

  • Dani S. Bassett, PhD

    Philadelphia, PA United States

  • Michael James Higley, MD, PhD

    New Haven, CT United States

  • Michael Henderson, PhD

    Grand Rapids, MI United States

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