Evidence that Parkinson's starts in the gut reaffirmed in new study

New findings by Columbia researchers and graduate students are adding to evidence backing this hypothesis-and showing that what triggers initial gastrointestinal changes in Parkinson’s could be a misdirected immune attack. The findings also raise the possibility that early detection-and then interruption-of an immune response in the gut could prevent a later attack on the brain’s neurons and stop Parkinson’s in its tracks.

In Parkinson’s, a protein called alpha-synuclein becomes misfolded, accumulates inside neurons, and slowly poisons the cells. Sulzer’s lab in collaboration with immunologists at the La Jolla Institute of Immunology has shown that small portions of the misfolded alpha-synuclein also can appear on the outside of neurons, which makes the neurons vulnerable to attack from the immune system. The immune attack could be doing more acute damage to the neurons than the internal deposits of alpha synuclein.

To find out if an immune reaction to alpha-synuclein can kick-start the disease and where, they, first created a mouse capable of displaying pieces of misfolded alpha-synuclein on cell surfaces. They then injected the mice with alpha-synuclein and monitored what happened in the brain and the gut.

The researchers did not see any signs resembling Parkinson’s disease in the brain, but they did see that an immune attack on neurons in the gut produced constipation and other gastrointestinal effects resembling those seen in most Parkinson’s patients years before they are diagnosed with the disease.

Reference: Interaction of an α-synuclein epitope with HLA-DRB1∗15:01 triggers enteric features in mice reminiscent of prodromal Parkinson’s disease, Neuron, DOI 10.1016/j.neuron.2023.07.015