Investigator:
Patricia Aguilar Calvo, PhD
Name of Institution:
University of Alabama at Birmingham
Project Title:
Heparan-sulfate mediated mechanisms of a-synuclein propagation in Parkinson’s disease
Investigator Bio:
Dr. Aguilar Calvo is a veterinary graduate of the Universidad Complutense in Madrid (Spain). She earned a federal fellowship to perform her thesis training under Dr. Juan Maria Torres at the National Center for Agricultural and Food Research and Technology (INIA). As a graduate student, Dr. Aguilar Calvo assessed the genetic resistance of multiple mammal species to prion diseases. Based on her research findings, selective breeding programs to eliminate prion diseases in sheep and goats were successfully implemented in the European Union.
Dr. Aguilar Calvo performed postdoctoral research at the University of California San Diego with Dr. Christina Sigurdson, where she focused on the host factors that modulate the emergence of prion strains and the role of heparan sulfate proteoglycans in the progression of prion disease and Alzheimer’s disease (AD) pathology. Dr. Aguilar Calvo discovered heparan sulfate proteoglycans as major host cofactors in the replication and accumulation of prions and amyloid-beta in brain. The Aguilar Calvo Lab also found that heparan sulfate proteoglycans promote the internalization of alpha-synuclein (a-syn) aggregates in cultured neurons. The lab’s current focus is understanding the role of heparan sulfate proteoglycans in the propagation and clearance of a-syn aggregates during Parkinson’s disease (PD) progression.
Dr. Aguilar Calvo’s research career has been continuously funded by federal and private institutions including a Predoctoral Training Grant from the Spanish Ministry of Science and Innovation, a Postdoctoral Training Grant from the Ramón Areces Foundation, and a K99/R00 Pathway to Independence Award from NIH.
Objective:
To understand how heparan sulfate proteoglycans modulate the propagation and clearance of a-syn aggregates in the nervous system.
Background:
Mounting evidence suggests that a-syn aggregation occurs in restricted areas of the nervous system and then spreads between connected neurons. Impairing the cell-to-cell propagation of a-syn aggregates could therefore slow PD progression. Our studies in cortical neurons show that heparan sulfate proteoglycans are the main receptors for the incorporation of a-syn aggregates. However, the role of heparan sulfate proteoglycans in the progression of PD pathology has never been investigated. Here we propose to use mouse models deficient of heparan sulfate sulfation to determine the role of heparan sulfate proteoglycans in the in-vivo propagation of a-syn fibrillar aggregates.
Methods/Design:
In this proposal, we will determine the role of heparan sulfate proteoglycans in the cell-to-cell propagation and aggregation of a-synuclein proteins in vivo with mouse models deficient in heparan sulfate sulfation. We will measure how decreasing heparan sulfate sulfation impacts the levels and distribution of a-synuclein inclusions, the loss of dopaminergic neurons and the length of a-syn fibrils after the intracerebral injection of a-syn preformed fibrils (PFFs) and monomers. We will also use positron emission tomography scanning to evaluate if decreasing heparan sulfation impacts the distribution of a-synuclein fibrils in the central nervous system.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
These studies will provide valuable information on the molecular mechanisms underlying the cell-to-cell propagation and clearance of a-syn fibrils to discover new targets for the rational design of neuroprotective therapies for PD.