Protein discovery could lead to new Parkinson’s treatments

Two proteins on motor neurons in the brain may drive the progression of Parkinson’s, new research suggests.

Parkinson’s is a neurodegenerative condition in which neurons slowly die. A misfolded protein called α-synuclein builds up and spreads between cells, damaging brain tissue.

A new study points to two membrane proteins, mGluR4 and NPDC1, as major players in moving misfolded α-synuclein into healthy neurons after it escapes from dying neurons.

The research, conducted by Yale School of Medicine, could aid more effective treatments, says senior author Stephen Strittmatter, professor of neurology and chair of the department of neuroscience.

Misfolded α-synuclein is “the pathological hallmark of Parkinson’s disease.” He added: “If we understood how it gets into neurons, we could perhaps block or slow down the progression of the disease.”

“We need to understand the molecular mechanism of how it spreads.”

The Parkinson’s Foundation estimates that about 1.1 million Americans are living with the condition, and nearly 90,000 more are diagnosed each year.

People with Parkinson’s often have motor symptoms such as tremor, balance problems and slowed movement. As α-synuclein builds up in motor cells and spreads, symptoms worsen.

To test whether α-synuclein enters new cells by binding to surface proteins, the team created 4,400 batches of cells, each expressing different cell surface proteins, and watched for binding to misfolded α-synuclein.

Most surface proteins did not bind. Sixteen did, including two present in human dopamine neurons of the substantia nigra, a brain region that degenerates in Parkinson’s. The researchers found that mGluR4 and NPDC1 transported misfolded α-synuclein into cells.

They then genetically modified mice so either mGluR4 or NPDC1 was nonfunctional and introduced misfolded α-synuclein.

In regular mice, misfolded α-synuclein accumulated in the brain and the animals developed Parkinson’s-like symptoms. Mice lacking working mGluR4 or NPDC1 did not. Knocking out the genes for these surface proteins in a mouse model of Parkinson’s reduced the risk of death and slowed symptom progression.

The findings suggest a potential route to new treatments. Current approaches mainly relieve symptoms but do not effectively stop progression. Targeting the spread of α-synuclein could slow or halt the disease course.

Strittmatter said: “We have an ageing population. How we can stop or slow neurons from dying is an enormous problem. This is really the time to make some inroads into figuring out how to slow it down.”