Changes in synaptic vesicle-binding of alpha-synuclein as an early biomarker for synucleinopathies
Project Number1R01NS136423-01A1
Former Number1R01NS136423-01A1
Contact PI/Project LeaderBURRE, JACQUELINE Other PIs
Awardee OrganizationWEILL MEDICAL COLL OF CORNELL UNIV
Description
Abstract Text
PROJECT SUMMARY/ABSTRACT
Aggregation of α-Synuclein (αSyn) in brain Lewy bodies (LB) is a key pathological feature in Parkinson’s dis-
ease (PD) and Alzheimer’s disease related dementias (ADRD) including Lewy body dementia (LBD). The neu-
rodegeneration that leads to PD and LBD precedes diagnosis by up to a decade or more, with constipation
being one of the earliest symptoms. LBs are found also in the enteric nervous system, which, unlike the brain,
is readily accessible through routine screening colonoscopy. Yet, the initial events leading to αSyn aggregation
remain unclear. While no single biomarker is sufficiently specific so far for routine use in the diagnostic or
prognostic disease evaluation, αSyn has emerged as a leading therapeutic target because it is a central player
in PD and ADRDs. αSyn binding to synaptic vesicle membranes defines its physiological and pathological
roles. We found that a reduction in synaptic vesicle binding in the brain is predictive of αSyn aggregation. Yet,
a detailed biochemical analysis of αSyn membrane binding in the gut has never been done. The objective in
this application is to determine changes in synaptic vesicle-binding of αSyn in neurons of the ENS and the
brain. The central hypothesis is that changes in synaptic vesicle-binding of αSyn can serve as an early bi-
omarker of PD and ADRD such as LBD. This hypothesis will be tested in two specific aims: 1) Identify the GI
area with the most prominent changes in synaptic vesicle-binding of αSyn; 2) Establish a timeline of changes
in synaptic vesicle-binding of αSyn. Under the first aim, four gut areas of 10-month-old αSynBAC mice, a mild
synucleinopathy model, and fresh biopsies taken from similar areas in humans during routine screening colon-
oscopy will be analyzed by subcellular fractionation and quantitative immunoblotting, and immunohistochemis-
try. Under the second aim, motor and GI function will be assessed in αSynBAC mice at weekly intervals from 1
month of age (before onset of symptoms) and 3 months of age (when symptoms are present). Changes will be
correlated with total and membrane-bound levels of αSyn in the brain and gut of these mice, and with changes
in neuron density, synapse density and gliosis. Same readouts will be applied to gut biopsies from subjects
with severe and mild PD and subjects at risk for developing PD. This study is expected to show a reduction in
synaptic vesicle-binding of αSyn as a function of disease severity in the gut of human subjects and our αSyn-
BAC mice, and that this reduction can be utilized as an early prodromal disease biomarker. This research is in-
novative because it represents the first biochemical assessment of αSyn in the neurons of the gut and because
of our use of fresh biopsies taken during routine cancer screening colonoscopies, enabling biochemical frac-
tionation. This work is significant because it will lead to a better understanding of pathogenic changes in αSyn,
may provide a better understanding of neuronal vulnerability in the gut and brain, and may lead to the devel-
opment of a new biomarker for PD and ADRDs/LBD, targeting prodromal disease.
Public Health Relevance Statement
PROJECT NARRATIVE
The proposed research is relevant to public health because alpha-synuclein pathology is linked to neurological
diseases including Parkinson’s disease, Alzheimer Disease related dementias such as Dementia with Lewy
bodies, Multiple System Atrophy, and other synucleinopathies, and understanding early pathogenic events that
trigger alpha-synuclein pathology will allow us to better understand the underlying disease mechanisms and
develop novel intervention therapies aimed at prodromal disease stages. Thus, this research is relevant to the
NIH’s mission that pertains to supporting the ongoing basic research, foster research that has immediate
medical relevance, and encourage translational research that links the discoveries from basic research into
therapeutic interventions for treating neurological disorders such as Parkinson’s disease and Dementia with
Lewy bodies.
NIH Spending Category
No NIH Spending Category available.
Project Terms
AcetylationAgeAge MonthsAlzheimer's disease related dementiaAmerican Cancer SocietyAreaAutopsyBacterial Artificial ChromosomesBasic ScienceBindingBiochemicalBiological AssayBiological MarkersBiopsyBrainCecumCell FractionationClinicalColonColonoscopyConstipationDataDementia with Lewy BodiesDepositionDetectionDevelopmentDiagnosisDiagnosticDiseaseEnteric Nervous SystemEvaluationEventFosteringFractionationFunctional disorderFutureGeneral PopulationGeneticGliosisGoalsGuidelinesHumanImageImmunohistochemistryLewy BodiesLewy Body DementiaLewy neuritesLinkMeasuresMedicalMembraneMissionModelingMorphologic artifactsMotorMultiple System AtrophyMusN-terminalNerve DegenerationNervous System DisorderNeuronsNeuroprotective AgentsParkinson DiseasePathogenesisPathogenicityPathologicPathologyPatientsPhosphorylationPhysiologicalPublic HealthREM Sleep Behavior DisorderRecombinantsRectumResearchRiskRisk FactorsRoleScreening for cancerSeverity of illnessSigmoid colonSubstantia nigra structureSymptomsSynapsesSynaptic VesiclesTestingTherapeutic InterventionTissue ExtractsTissuesTranslational ResearchUnited States National Institutes of HealthWestern BlottingWorkalpha synucleinbrain tissuecohortcomparison controldensitydisease diagnosisdisease prognosticdopaminergic neuronearly detection biomarkersgenetic risk factorhigh riskhuman subjectileuminnovationmotor behaviormotor symptommouse modelneuropathologynovelprognosticroutine screeningscreening guidelinessynucleinopathytherapeutic targettimeline
National Institute of Neurological Disorders and Stroke
CFDA Code
853
DUNS Number
060217502
UEI
YNT8TCJH8FQ8
Project Start Date
01-December-2024
Project End Date
30-November-2029
Budget Start Date
01-December-2024
Budget End Date
30-November-2025
Project Funding Information for 2025
Total Funding
$793,535
Direct Costs
$469,456
Indirect Costs
$324,079
Year
Funding IC
FY Total Cost by IC
2025
National Institute of Neurological Disorders and Stroke
$793,535
Year
Funding IC
FY Total Cost by IC
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