New MJFF, NIH grants to fund key research into early Parkinson’s
Scientists aim to use preclinical models to help ID symptoms earlier
The Michael J. Fox Foundation for Parkinson’s Research (MJFF) has awarded a $697,000 grant to a research project using preclinical models to study early Parkinson’s disease linked to mutations in the PINK1 gene.
Cynthia Kelm-Nelson, PhD, a department of surgery senior scientist, will lead the three-year project at the University of Wisconsin. The researcher also received a renewal of a National Institutes of Health (NIH) grant — amounting to $2.66 million over five additional years — to continue investigating the role of inflammation in vocal deficits within a preclinical Parkinson’s model.
In people, about 9 in 10 individuals with Parkinson’s experience difficulties with speech. A university news story about the new grants notes that part of Kelm-Nelson’s work, using a rat model of Parkinson’s, will be to “determine whether existing anti-inflammatory drugs can be used to improve vocal communication dysfunction that is related to this disease.”
Overall, according to Kelm-Nelson, “earlier identification of the signs and symptoms of the disease could help us intervene earlier, reducing both the progression of the disease over time and the burden it places on patients and the economy as a whole. To do that, we need rigorously validated preclinical models that we can study, which will in turn help us better pinpoint the origins of early-stage disease.”
Parkinson’s disease is caused by the progressive loss of dopaminergic neurons, nerve cells that produce dopamine, a signaling molecule involved in motor control. While the exact cause of the loss of these neurons is not fully known, in some cases, genetic mutations, including those found in the PINK1 gene, are involved in the disease.
Early Parkinson’s symptoms can start 20 years before diagnosis
Although the disease is usually diagnosed in people between 60 and 65, brain changes and nonspecific symptoms, including vocalizations and changes in how individuals move, may begin up to 20 years earlier.
The now-funded study, “Phenotypic and Construct Validity of Pink1-/- in Preclinical Models for Preclinical Parkinson’s Research,” will evaluate Parkinson’s-like symptoms in two rat preclinical models of early-onset Parkinson’s associated with mutations in the PINK1 gene. One is a commonly used model, and the other is a novel one developed by MJFF using CRISPR genetic engineering technology.
Preclinical models provide valuable tools for investigating the mechanisms underlying Parkinson’s, which are often difficult to study directly in humans. This work aims to determine whether such models can also be used to examine the early, prediagnostic stages of the disease.
Researchers hypothesize that the new model will present changes in the brainstem, a region at the bottom of the brain where the disease likely begins, and may show early brain and behavioral changes similar to what happens in humans.
Using both models, researchers will test their vocalizations and movements using standard rat behavioral tests and measure the levels of dopamine and protein clumps in their brains. Protein clumps, mainly composed of the alpha-synuclein protein, are thought to drive neuronal dysfunction and death in Parkinson’s disease.
These models are useful research tools because they can be used as a model of the disease, [and] they allow researchers to ask questions that are impossible to study in humans. … The goal of this work is to see how helpful these models are for scientists who are studying the early stage of Parkinson’s disease, before it is officially diagnosed.
The study will include both male and female rats to increase the generalizability and translatability of the research findings to humans. Ultimately, the project’s results may allow researchers to select the preclinical model that most closely mimics the early human disease for further studies.
The renewal of the NIH grant will further enable the team to investigate how inflammation affects vocal pathways in the brain and contributes to vocal deficits. Using the rat model of Parkinson’s associated with PINK1 mutations, the researchers will also examine whether anti-inflammatory drugs can improve vocal communication.
“These models are useful research tools because they can be used as a model of the disease, [and] they allow researchers to ask questions that are impossible to study in humans,” the researchers wrote in a study rationale shared on the MJFF’s website. “The goal of this work is to see how helpful these models are for scientists who are studying the early stage of Parkinson’s disease, before it is officially diagnosed.”
The team stated that they believe this new model will show “clear and consistent changes in the brainstem … that more closely match the early stages of Parkinson’s in humans.”
Kelm-Nelson added: “We’re incredibly grateful to both the MJFF and the NIH for their support as we pursue both of these lines of research.”
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