$3M federal grant will allow study of protein causing Parkinson’s dementia
Colorado State University team to target distinct variant of alpha-synuclein
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- A $3 million federal grant will fund new research into how a distinct variant of the alpha-synuclein protein contributes to Parkinson’s disease dementia.
- The National Institutes of Health award allows scientists from Colorado State University to build on their earlier work in a mouse model of the disease.
- The team is aiming to develop better diagnostic tools and future disease-halting therapies for people with Parkinson's.
A team at Colorado State University (CSU) has been awarded $3 million from the National Institutes of Health (NIH) to investigate how a distinct variant of the alpha-synuclein protein — which can build up into toxic clumps in the brain — contributes to Parkinson’s disease with dementia.
The federal grant will allow the university’s researchers to study how this variant spreads through the nervous system. The team’s ultimate goal is to develop therapies to stop the disease’s progression, according to a university news story announcing the funding.
The five-year project, led by Amanda Woerman, PhD, an associate professor at CSU, will build on the team’s previous identification of a unique alpha-synuclein variant in a person with Parkinson’s disease dementia. The researchers will now try to determine how this variant may contribute to the disease’s progression — potentially informing future diagnostic and treatment approaches.
“We’re getting closer to understanding what drives these types of diseases,” Woerman said. “If we can learn how this specific variant causes Parkinson’s with dementia, it will help us better understand what we need to do to successfully intervene and stop the disease.”
Parkinson’s is caused by the loss of nerve cells that produce dopamine, a signaling molecule involved in movement. A hallmark feature of Parkinson’s is the buildup of toxic clumps of misfolded alpha-synuclein protein, known as Lewy bodies, which are believed to contribute to nerve cell dysfunction and death. Alpha-synuclein is a small protein key to nerve cell communication.
While Parkinson’s is best known for its hallmark motor symptoms, such as tremor, stiffness, and slowed movements, people with the progressive disease may also experience cognitive decline and dementia. Known as Parkinson’s disease dementia, the condition refers to a decline in memory, attention, and thinking that interferes with everyday activities.
Colorado State team discovered variant in lab testing
Prior studies have demonstrated that misfolded alpha-synuclein may adopt different structures, or conformations, that are associated with distinct effects on patients. Woerman’s lab found that a particular variant of the protein could trigger neurological disease in a mouse model.
In that study, the researchers found that a post-mortem brain sample from a person with Parkinson’s disease dementia contained a distinct form of misfolded alpha-synuclein. The team tested it in mice and reported their findings in a study titled “Evidence of a novel α-synuclein strain isolated from a Parkinson’s disease with dementia patient sample,” published in the journal Acta Neuropathologica Communications.
The data showed that four of six mice developed abnormal alpha-synuclein clumps in several brain regions and neurological symptoms after receiving the patient-derived sample. Further experiments suggested that this strain differed from the alpha-synuclein strain linked to multiple system atrophy (MSA), pointing to potentially distinct ways that alpha-synuclein can spread through the brain.
MSA is a form of atypical Parkinsonism also marked by alpha-synuclein clumping, which has many of the motor symptoms seen in Parkinson’s. However, it usually causes greater impairment of the autonomic nervous system, which regulates unconscious bodily processes, and progresses faster than Parkinson’s.
The patient’s brain showed Lewy bodies typical of Parkinson’s disease dementia, but also had alpha-synuclein deposits in oligodendrocytes, a type of nerve supporting cell, which are characteristic of MSA. This led researchers to question whether an MSA-like alpha-synuclein strain was responsible for the disease in mice.
When the scientists transferred material from the affected mice to a second group, the disease progressed faster and led to more widespread alpha-synuclein buildup in the brain. However, the pattern of symptoms and brain changes differed from those caused by MSA, suggesting the patient had a distinct, previously unrecognized alpha-synuclein variant, according to the researchers.
This work will give us insight into how we might be able to successfully fight Parkinson’s. … The ultimate goal is to develop a successful cure for somebody living with one of these disorders.
The NIH-funded project will build on the researchers’ discovery of this previously unrecognized alpha-synuclein variant to investigate how its molecular structure influences where the protein spreads in the brain and how it contributes to dementia and other disease features.
The long-term goal is to use insights into alpha-synuclein biology to support the development of better diagnostic tools and treatments for people with Parkinson’s and other diseases caused by alpha-synuclein clumping.
“This work will give us insight into how we might be able to successfully fight Parkinson’s,” Woerman said. “The ultimate goal is to develop a successful cure for somebody living with one of these disorders.”
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