Overview
Neurons communicate via release of neurotransmitters from presynaptic terminals. This requires intact functioning of the protein expression and trafficking machinery, of mitochondria to meet a synapses’ need for energy, of the proteasome/ubiquitin system and lysosomes to clear aged and misfolded proteins, and of the synaptic vesicle cycle to mediate continuous neurotransmission. Much evidence points to presynaptic terminals as initiation site for neurodegeneration in diseases such as Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease, where synaptic dysfunction has been shownto precede neuron death and to occur long before neuropathological symptoms become apparent. Yet, virtually nothing is known about processes involved.
We are interested in early pathological events at the synapse which trigger neurological disorders and neurodegeneration. We will approach this topic by investigating the dysfunction of synucleins at the synapse, a protein family implicated in Parkinson’s Disease, Alzheimer’s Disease, multiple system atrophy, and dementia with Lewy bodies; by investigating the dysfunction of Munc18 at the synapse with regards to Ohtahara syndrome (early infantile epileptic encephalopathy) and mental retardation with non-syndromic epilepsy; and by an exploratory screen to identify other yet-unknown mechanisms triggering synaptic dysfunction and degeneration in various diseases. To address these aims, we will employ an array of cutting-edge technologies, including biophysics, biochemistry, cell biology, imaging, and mouse models of neuropathology.
We envision that defining early pathological events at the synapse will provide new avenues for preventing and/or treating neurodegenerative diseases in humans.
Highlights
- 1Cell reports · 2022
- 2Nature communications · 2025
- 3EMBO molecular medicine · 2020
Publications
Funding
Active
9 grants- MPIR01NS136423-02Changes in synaptic vesicle-binding of alpha-synuclein as an early biomarker for synucleinopathiesNational Institute of Neurological Disorders and Stroke · 2024–2029
- MPIR01AG083949-01A1Tau proteostasis by chaperone-complexes in tauopathies including Alzheimer's diseaseNational Institute on Aging · 2024–2029
- KPAPDA 251556-01Synaptic vesicle lipid dyshomeostasis in synucleinopathiesAmerican Parkinson Disease Association · 2025–2027
- Co-IUL1TR002384-06Clinical and Translational Science Center - UL1National Center for Advancing Translational Sciences · 2022–2027
- MPIR01NS126342-03The impact of beta- and gamma-synucleins on alpha-synuclein's synaptic functionNational Institute of Neurological Disorders and Stroke · 2022–2027
- Sub-PIR01NS121077-05The role of VAMP2 in alpha-synuclein function and pathologyNational Institute of Neurological Disorders and Stroke · 2021–2027 · via University of Cincinnati
- Sub-PIR21NS127002-02A novel gene therapy approach to prevent alpha-synuclein misfolding in multiple system atrophyNational Institute of Neurological Disorders and Stroke · 2023–2026 · via Colorado State University
- PIR01NS113960-05The impact of synaptic vesicle-binding of alpha-synuclein on neuron function and neuropathologyNational Institute of Neurological Disorders and Stroke · 2020–2026· 2 renewals
- KPUA 234565-01Dissecting STXBP1 dysfunction in a novel mouse model of STXBP1 EncephalopathiesUplifting Athletes · 2024–2026
Completed grants (11)
- PIR21NS127939-01Synaptic vesicle changes in synucleinopathiesNational Institute of Neurological Disorders and Stroke · 2022–2025
- KPF31NS130894-01A1Leveraging the genetics and biochemistry of UNC-13 to uncover mechanisms driving neurotransmitter secretionNational Institute of Neurological Disorders and Stroke · 2023–2025Fellowship
- KPF30HD100096-01A1Munc18-1 mutations disrupt syntaxin-5 stability and general secretory traffickingEunice Kennedy Shriver National Institute of Child Health and Human Development · 2020–2024
- PIRF1NS126342-01S1The impact of beta- and gamma-synucleins on alpha-synuclein's synaptic functionNational Institute of Neurological Disorders and Stroke · 2023–2024
- PIR01NS102181-05Molecular Mechanisms of Munc18-1 Linked Infantile Seizure Disorders and Rational Rescue StrategiesNational Institute of Neurological Disorders and Stroke · 2017–2024
- KPAES 222711-01Rescue of STXBP1 encephalopathies with 4-phenylbutyrate in a mouse modelAmerican Epilepsy Society · 2022–2023
- KPF31NS125949-01A1The role of beta-synuclein in synaptic vesicle releaseNational Institute of Neurological Disorders and Stroke · 2022–2023
- PIMDBR-22-113- STXBP1Rescue of STXBP1 encephalopathies with small molecules in mouse models in vivoOrphan Disease Center at University of Pennsylvania · 2022–2023
- PIAddgene 699480Addgene 699480Addgene, Inc. · 2022–2023
- PIAAN 222558-01AAN awardAmerican Academy of Neurology · 2021–2022
- PIMJFF 16164Stabilization of synaptic vesicle-bound alpha-synuclein to reduce alpha-synuclein aggregation and pathology in Parkinson's diseaseMichael J. Fox Foundation for Parkinson's Research · 2019–2020
Mentoring
- KCKathryn CarnazzaNeuroscience (PhD) · Class of 2022
- LKLauren KomerNeuroscience (PhD) · Class of 2023
- APAndre PinedaNeuroscience (PhD) · Class of 2019
- ABAniv BruknerPostdoc mentee · 2020–2023
- DADebra AbramovMD PhD student · Class of 2023
- ACAbigail CrossNeuroscience (PhD)