Unveiling the Unexpected Origins of Parkinson’s Disease

An autoimmune response in mice to a protein related to Parkinson’s illness broken neurons in the GI tract, including to proof that the illness might get its start in the intestine. Credit: David Sulzer, Columbia University Irving Medical Center

Ask any neurologist they usually’ll let you know: Parkinson’s illness is a dysfunction of the mind. The unmistakable indicators of this ailment, resembling involuntary shaking, decreased motion velocity, and the sensation of one’s toes being glued to the flooring, originate from the loss of neurons in a mind space chargeable for motion regulation.

However, a rising quantity of scientists theorize that the roots of this neurodegenerative situation may be traced again to the intestine, probably manifesting lengthy earlier than any neurological signs emerge.

New findings by Columbia researchers David Sulzer, Ph.D., and Dritan Agalliu, Ph.D., and two of their graduate college students are including to proof backing this speculation—and exhibiting that what triggers preliminary gastrointestinal modifications in Parkinson’s could possibly be a misdirected immune assault.

“If this is the beginning of Parkinson’s in many people, we could potentially identify who has the disease before it ever reaches the brain and hopefully stop it in its tracks,” Sulzer says. The new findings have been just lately revealed in the journal Neuron.

Autoimmunity and the intestine

The gut-first idea of Parkinson’s, initially proposed 20 years in the past, started to intrigue Sulzer after his personal analysis pointed towards the position of an autoimmune response in Parkinson’s.

In Parkinson’s, a protein referred to as alpha-synuclein turns into misfolded, accumulates inside neurons, and slowly poisons the cells. Sulzer’s lab in collaboration with immunologists at the La Jolla Institute of Immunology has proven that small parts of the misfolded alpha-synuclein can also seem on the outdoors of neurons, which makes the neurons susceptible to assault from the immune system. The immune assault could possibly be doing extra acute harm to the neurons than the inside deposits of alpha-synuclein.

“The blood of Parkinson’s patients often contains immune cells that are primed to attack the neurons,” Sulzer says, “but it’s not clear where or when they are primed.”

The intestine was an intriguing risk as a result of it comprises the identical neurons and since most Parkinson’s sufferers expertise constipation years earlier than mind signs emerge and the illness is identified. To pursue this speculation, Sulzer teamed up with Agalliu, a neuroimmunologist with experience in mouse fashions of one other neurological dysfunction (a number of sclerosis) that has autoimmune options.

Immune response to alpha-synuclein results in intestine signs

To discover out if an immune response to alpha-synuclein can kick-start the illness and the place, Francesca Garretti and Connor Monahan, grad college students directed by Agalliu and Sulzer, first created a mouse succesful of displaying items of misfolded alpha-synuclein on cell surfaces (pure mice do not need this means). They then injected the mice with alpha-synuclein and monitored what occurred in the mind and the intestine.

The researchers didn’t see any indicators resembling Parkinson’s illness in the mind, however they did see that an immune assault on neurons in the intestine produced constipation and different gastrointestinal results resembling these seen in most Parkinson’s sufferers years earlier than they’re identified with the illness.

“This shows that an autoimmune reaction can lead to what appears to be the early stages of Parkinson’s and is strong support that Parkinson’s is in part an autoimmune disease,” Sulzer says.

The findings additionally elevate the risk that early detection—after which interruption—of an immune response in the intestine might forestall a later assault on the mind’s neurons and cease Parkinson’s in its tracks.

Wanted: A mouse with Parkinson’s illness

Right now, although, it’s not clear how huge a job the immune system performs in the Parkinson’s mind. The reply to that query might turn into clearer if the researchers discover out why the brains of their mice didn’t develop any indicators of Parkinson’s.

The staff hypothesizes that the immune cells of their mouse mannequin will not be reaching the mind as a result of the animals are younger and age has not but weakened the blood-brain barrier sufficiently to let immune cells squeeze by way of. Opening the barrier or accelerating the growing old course of might result in mice that develop gastrointestinal and mind signs.

“Our ultimate goal is to develop a model of Parkinson’s disease in mice that recreates the human disease process, which doesn’t exist right now,” Sulzer says. “That will be critical in answering questions about the disease that we can’t explore in people and eventually developing better therapies.”

Reference: “Interaction of an α-synuclein epitope with HLA-DRB1∗15:01 triggers enteric features in mice reminiscent of prodromal Parkinson’s disease” by Francesca Garretti, Connor Monahan, Nicholas Sloan, Jamie Bergen, Sanjid Shahriar, Seon Woo Kim, Alessandro Sette, Tyler Cutforth, Ellen Kanter, Dritan Agalliu and David Sulzer, 18 August 2023, Neuron.
DOI: 10.1016/j.neuron.2023.07.015

This analysis was funded by Aligning Science Across Parkinson’s by way of the Michael J. Fox Foundation for Parkinson’s Research, the National Institutes of Health; the JPB Foundation; the National MS Society, and presents from Newport Equities LLC, the Walz household, and PANDAS Network to the Department of Neurology at Columbia University.

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