Neuroprotective Effects of Carnosine in the Olfactory System in the Thy1-aSyn Mouse Model of Parkinson s Disease
Abstract
According to the Parkinson’s Disease (PD) Foundation, as many as 1 million Americans are currently living with PD, with 60,000 new cases diagnosed per year, and more than 10 million people living with the disease world-wide. An important early clinical manifestation of PD is diminished olfaction (sense of smell). Olfactory function is essential for human health and well-being. Loss of olfactory function results in risk of harm due to the inability to detect hazards, such as fire, chemical spills, and spoiled food. Humans with reduced olfactory function, including those with PD, also report loss of pleasure associated with eating food, and many people, particularly the elderly, who suffer from disease- or age-related decline in olfactory function, do not eat properly. A key pathological feature of PD is aggregation of the protein alpha-synuclein (aSyn), which leads to death of neurons in various regions of the brain that regulate olfactory and motor function. We identified a naturally occurring molecule, named carnosine, that is reported to have the ability to prevent protein aggregation and potentially improve the function of nerve cells. Many laboratory mouse and rat strains have been developed that display various features of PD, such as olfactory and motor deficits. We chose to study PD in a mouse model called the Thy1-aSyn model, which displays many of the early behavioral and pathological features of PD, including olfactory dysfunction and motor deficits. Further, realizing the close connection between the nose and the brain, we began pilot studies wherein we treated Thy1-aSyn mice with carnosine by intranasal administration. Preliminary results show two important benefits of intranasal carnosine treatment: decreased aSyn aggregation in the region of the nasal cavity that is responsible for the sense of smell (the olfactory epithelium) and slowed progression of the locomotor deficits that develop in this mouse model of PD. This proposal was prepared in response to the Focus Idea Award goal of “identification and evaluation of mechanisms in early Parkinson’s disease involving olfactory, microbiome, gastrointestinal, and/or autonomic nervous systems.” Given our background and expertise, our proposal focuses primarily on reducing the progression of olfactory dysfunction in PD. Our proposed studies will robustly examine the potential for carnosine treatment to slow or reverse olfactory dysfunction by treating Thy1-aSyn mice via two routes of exposure (intranasal and oral) to determine which route may be more beneficial for human PD patients. To address the possible mechanistic basis of the disease, we will also study the effects of carnosine on regulation of genes in the olfactory epithelium to potentially learn of new molecular pathways that might be important drug targets and ultimately benefit PD patients. If, as we believe, aSyn accumulation is a pivotal step in the development and progression of PD, then new methods to prevent aSyn aggregation should provide protection against the development and progression of not only olfactory dysfunction in PD, but also other key debilitating symptoms of the disease, including motor dysfunction, and mood disorders (anxiety and depression).
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710699
Entities
People
- Mary Beth Genter
Organizations
- United States Army
- University of Cincinnati