Reduced Levels of Chaperone Protein May Advance Parkinson’s, Other Dementias, Study Finds
The protein may be a promising therapeutic target to treat Parkinson’s, with researchers pursuing this possibility in preclinical studies.
The study, “14-3-3 proteins reduce cell-to-cell transfer and propagation of pathogenic alpha-synuclein,” was published in The Journal of Neuroscience.
Development of Parkinson’s disease and Lewy body dementia has been tightly linked with the formation of misfolded clumps of the alpha-synuclein protein inside nerve cells. These aggregates contribute to the nerve cell death and neurodegeneration that characterize these diseases.
Once formed, misfolded alpha-synuclein clumps can be spread from one brain region to another, thereby advancing the disease. But not much has been known about the mechanisms underlying the transmission between affected and healthy nerve cells.
University of Alabama at Birmingham researchers investigated the role of a protein they thought could potentially play a part in this process. The protein, called 14-3-3θ, is a chaperone — a type of protein that can assist other proteins to assume a proper shape — highly expressed in the brain, essential for nerve cell functioning, and known to interact with alpha-synuclein.
Proteins need to have their proper shape to interact with other structures. Failure to do so, called misfolding, can result in a number of diseases.
Researchers used both human and mouse nerve cells grown in the laboratory to investigate the role of 14-3-3θ in the formation and spread of alpha-synuclein aggregates.
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Inhibiting 14-3-3θ promoted the aggregation and spread of alpha-synuclein from neuron to neuron, resulting in increased nerve cell death. Conversely, higher levels of 14-3-3θ protein blocked alpha-synuclein clump formation and limited its transfer to other nerve cells, preventing cell death.
“Our findings indicate that 14-3-3θ plays an important role in the management of alpha-synuclein, keeping it in a more normal folded state and preventing the spread of aggregates across the brain,” Talene Yacoubian, an MD and PhD, associate professor in the Department of Neurology at UAB and senior author of the study, said in a news release.
“The study suggests that 14-3-3θ may be a suitable target for efforts to slow the progression of neurodegenerative diseases, although more work is needed,” she said.
There is evidence that 14-3-3θ levels in the brain decrease as people age. Because Parkinson’s and Lewy body dementia are mostly diseases of aging, it further suggests that 14-3-3θ as a chaperone could become a potential therapeutic target.
“If subsequent research confirms our findings of its [14-3-3θ] role on preventing misfolding of alpha-synuclein, we may have a viable target for intervention in neurodegenerative diseases that are also age-related,” Yacoubian added.
The team has already began to conduct studies in animal models and is collaborating with the Southern Research Institute to find a compound suitable for human use that boosts the production of 14-3-3θ.