Jacob Ayers, Ph.D.
Department of Neuroscience
Center for Translational Research in Neurodegenerative Disease (CTRND)
1275 Center Drive
PO Box 100159
Gainesville, FL 32610-0159
Phone: (352) 294-5159
Mentor: Dr. David Borchelt
|Department of Neuroscience, University of Florida
Mentor: Dr. Anthony Kincaid
(Medical Microbiology & Immunology)
|University of New Hampshire
Key Words: Neurodegeneration, Amyotrophic Lateral Sclerosis, Protein Misfolding, Parkinson’s Disease, Prion, Propagation
My lab is focused on elucidating the mechanisms involved in the onset and propagation of neurodegenerative diseases. Over the last decade, a number of studies have implicated a prion-like mechanism for the accumulation and dissemination of proteins involved in Alzheimer’s Disease, Parkinson’s Disease, and Amyotrophic Lateral Sclerosis (ALS), among others. Taking a page from studies performed in the prion field, we have used both cell and animal models of these disorders to reveal that similar to the prion protein, these toxic misfolded proteins can template their structure onto natively folded proteins, thereby causing an accumulation of pathological inclusions. Additionally, we have demonstrated the ability for misfolded proteins implicated in ALS and Parkinson’s Disease to propagate throughout the central nervous system along known neuroanatomical pathways, most likely via axonal connections. By better understanding these properties, our hope is to develop therapies to prevent and/or stop the spread of these debilitating diseases.
Research Focus and Aims:
Project 1: Using the knowledge and techniques obtained from previous work in the prion field, I began investigating the potential prion-like properties of SOD1. My studies were the first that examined these properties in vivo. We revealed the permissiveness for the G85R-SOD1:YFP mouse model for MND transmission through the administration of misfolded SOD1 preparations including spinal cord homogenates from paralyzed mice and recombinant SOD1 protein. Using this model we have gone on to demonstrate the ability for SOD1 pathology to be induced locally and spread to synaptically linked populations of neurons and the existence of SOD1 strains. Additionally, using an organotypic spinal cord slice culture assay prepared from G85R-SOD1:YFP mice, we have demonstrated the ability for spinal homogenates from human A4V SOD1-fALS patients are capable of inducing SOD1 pathology. These novel findings describe a number of prion-like properties inherent of the SOD1 protein and describe a unique mouse model and injection paradigm that result in a spreading symptomology that mirrors that observed in ALS patients.
Project 2: Similar to project 1, we are also investigating the mechanisms involved in the propagation of proteins implicated in other disorders, such as a-synuclein and tau. Using animal models, our goal is to achieve a focal accumulation of pathology in the central nervous system and follow the spread of this pathology over time. This will allow us to better understand the mechanisms involved and provide a good model to test various therapeutic agents aimed at preventing the propagation of disease.
Project 3: Recent data has demonstrated the presence of lymphatic vasculature in the CNS and its role in clearing the brain’s interstitial fluid and its waste products. Using advanced imaging techniques, researchers have demonstrated that following drainage out of the skull, the fluid is fed into the deep cervical lymph nodes. We have begun studies in transgenic mouse models to better understand how this drainage system is affected in neurodegenerative disorders. Specifically, we hope to determine whether the toxic proteins that build up in the brains of Alzheimer’s patients are detected in this newly described lymphatic system and/or any downstream tissues such as the cervical lymph nodes. These studies have the potential to lead to a better understanding of the Alzheimer’s Disease process and to highlight new avenues for drug targeting and for manipulating current therapies.