Grant Award: Department of Defense, Discovery Award

Robert Mercer, a Postdoctoral Associate in the Harris Lab, was recently awarded a Discovery Award research grant funded by the Department of Defense. This two-year, $200,000 grant is entitled “ Identification of Receptors for TAR DNA-binding Protein 43 (TDP-43) That Mediate Cellular Uptake and Neurotoxicity ”. This project aims to identify the cellular receptors of the pathological TDP-43 assemblies found in the brains of patients with  Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Lobar Degeneration (FTLD), and Chronic Traumatic Encephalopathy (CTE). The identification of these receptors will provide novel therapeutic targets to combat these devastating and currently untreatable diseases.

Grant Awards: Visualizing Alzheimer’s Disease

Ladan Amin  an Instructor in the Harris laboratory was recently awarded a R03 research grant, funded by the National Institute on Aging (NIA). This two-year, $200,000 grant is entitled “Use of super-resolution microscopy to visualize the interaction between Alzheimer therapeutic antibodies and Aβ aggregates”. This project aims to identify the molecular mechanism of action of several different clinical antibodies by localizing them on single Aβ aggregates. This information will contribute significantly to understanding the basic biology of amyloid and its role in Alzheimer’s disease, and will provide a fuller picture of molecular mechanisms responsible for detoxifying oligomers and enhancing their clearance.

Nhat Le receives Warren Alpert Distinguished Scholars Award

Congratulations to Dr. Nhat Le, a Postdoctoral Research Associate in the Harris lab, who was recently awarded a Warren Alpert Distinguished Scholars career development award. This two-year, $400,000 fellowship will fund Nhat’s work on a project entitled “Signaling Pathways Underlying Prion Neurotoxicity”. Her project aims to identify the mechanism underlying prion-induced synaptotoxicity using genomic, proteomic and pharmacological techniques in mouse and human neurons and in animal models.

New Research Discoveries: Prions and Synaptic Toxicity

In a new research study from the Harris laboratory in PLOS pathogens, first author Cheng Feng and collaborators defined a new pathway mediated by the p38 MAPK signaling pathway that was important for prion synaptic toxicity. Furthermore this research identified that perturbations in the actin cytoskeleton within dendritic spines resulted in deficits in synaptic transmission.

This study has received significant press coverage and appeared on the cover of PLOS pathogens.

Congratulations Harris lab.

New Research Discoveries: Prion proteins and neuron degeneration

A new paper in eLife from the Harris lab has uncovered a novel function for different domains of the prion protein. Bei Wu, an Instructor in the laboratory was lead author.

Prion diseases, or transmissible spongiform encephalopathies, comprise a group of fatal neurodegenerative disorders in humans and animals for which there are no effective treatments or cures. These diseases are caused by refolding of the cellular prion protein (PrPC) into an infectious isoform (PrPSc) that catalytically templates its abnormal conformation onto additional molecules of PrPC.A similar, prion-like process may play a role in other neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases and tauopathies, which are due to protein misfolding and aggregation. Here, using a combination of electrophysiological, cellular, and biophysical techniques, we show that the flexible, N-terminal domain of PrPC functions as a powerful toxicity-transducing effector whose activity is tightly regulated in cis by the globular C-terminal domain. Ligands binding to the N-terminal domain abolish the spontaneous ionic currents associated with neurotoxic mutants of PrP, and the isolated N-terminal domain induces currents when expressed in the absence of the C-terminal domain. Anti-PrP antibodies targeting epitopes in the C-terminal domain induce currents, and cause degeneration of dendrites on murine hippocampal neurons, effects that entirely dependent on the effector function of the N-terminus. NMR experiments demonstrate intramolecular docking between N- and C-terminal domains of PrPC, revealing a novel auto-inhibitory mechanism that regulates the functional activity of PrPC.

New Research Discoveries—Prion Synaptotoxicity

prionspines

Congratulations to Cheng Fang and colleagues in the Harris lab for their recent paper in PLOS Pathogens which developed an in vitro neuronal system in which to study the early assault by prions on brain cells of the infected host. This system provides new insights into the mechanisms responsible for prion neurotoxicity, and it provides a platform for characterizing different pathogenic forms of PrPSc and testing potential therapeutic agents.