Protein Works to Spread Toxic Clumps in Brain and Promote Parkinson’s, Study Finds

Protein Works to Spread Toxic Clumps in Brain and Promote Parkinson’s, Study Finds

Connexin-32 — a protein found in small channels between nerve cells and involved in cell-to-cell communication — works to progress Parkinson’s disease by binding to alpha-synuclein and spreading toxic protein clumps throughout the brain, research suggests.

The study, “Binding of α-synuclein oligomers to Cx32 facilitates protein uptake and transfer in neurons and oligodendrocytes,” was published in Acta Neuropathologica. It suggested that treatments targeting connexin-32 might help to prevent or slow disease progression.

Connexins are transmembrane proteins that form tiny channels (also known as gap junction channels), enabling communication between adjacent cells. Because connexins are expressed throughout the body and play various roles, their dysfunction is often associated with disease, including Parkinson’s, epilepsy, and Alzheimer’s.

Parkinson’s is characterized by a buildup in the brain of the protein alpha-synuclein, which forms clumps known as Lewy bodies that damage and kill nerve cells, or neurons.

“During the past few decades, we have realized that the protein deposits in the brain can spread between cells, acting as seeds that start a new aggregation cycle in the next cell. The disease in this way spreads in the brain in a manner similar to an infection,” study leader Martin Hallbeck, an associate professor in the Department of Clinical and Experimental Medicine at Linköping University in Sweden, said in a press release.

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Hallbeck’s team set out to determine and better understand mechanisms that might promote the spread of alpha-synuclein.

The researchers observed that connexin-32 selectively binds to abnormally clumped alpha-synuclein and transfers it to neighboring neurons, a possible explanation for how Parkinson’s progresses within the brain. Connexin-32 also helped propagate toxic forms of alpha-synuclein between oligodendrocytes — cells that play a key role in the production of myelin that insulates nerve cells.

Neurons and oligodendrocytes, respectively, are “the primary cell types highly vulnerable to α-syn [alpha-synuclein] accumulation” in Parkinson’s and a neurological disease called multiple system atrophy (MSA), the study noted.

Using pharmacological and genetic techniques, researchers found that connexin-32 overexpression (higher-than-normal levels) was associated with the transport of alpha-synuclein clumps. When scientists blocked connexin-32 activity, the spread of abnormal alpha-synuclein lowered in a concentration-dependent manner.

Rare mutations of multiplications in the alpha-synuclein (SNCA) gene have been associated with early onset forms of Parkinson’s disease. Researchers observed that high levels of connexin-32 were present in cells that either overexpressed SNCA or were exposed to alpha-synuclein aggregates.

High levels of connexin-32 that correlated with alpha-synuclein accumulation were also observed in nerve cells in a mouse model of Parkinson’s disease.

Working with brain tissue taken from four deceased Parkinson’s patients, researchers again saw a direct binding between alpha-synuclein and connexin-32 in samples from two patients but not in four age-matched healthy controls. This finding suggests that these two proteins interact in Parkinson’s but not in a healthy brain.

“Collectively, our results provide strong evidence for [connexin-32] centrally involved in the preferential uptake and propagation of [alpha-synuclein clump] assemblies, pinpointing [connexin-32] as a novel therapeutic target to impede the uptake and spread of [alpha-synuclein] pathology in [Parkinson’s disease] and related α-synucleinopathies,” investigators concluded.

“We hope that connexin-32 can be used in the future as a target for drug treatment,” Hallbeck added.

Catarina Silva, MSc BNS Writer
With over three years of experience in the medical communications business, Catarina holds a BSc. in Biomedical Sciences and a MSc. in Neurosciences. Apart from writing, she has been involved in patient-oriented translational and clinical research.
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Catarina Silva, MSc BNS Writer
With over three years of experience in the medical communications business, Catarina holds a BSc. in Biomedical Sciences and a MSc. in Neurosciences. Apart from writing, she has been involved in patient-oriented translational and clinical research.
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