The accumulation of a misfolded protein in the brain could activate immune cells to attack dopamine-forming neurons

In Parkinson's disease, particles of alpha-synuclein (dark brown) are deposited in neurons of the substantia nigra, a part of the midbrain.

New York (USA) - Faulty immune system responses could play an important role in the development of Parkinson's disease. As American physicians have now discovered, a disease-like protein in the brain causes the activation of immune cells, possibly attacking and destroying dopamine-forming neurons. It is still not clear whether this autoimmun reaction is one of the causes or a consequence of the neurodegenerative disease, the researchers report in the journal "Nature". The results suggest new approaches to immunotherapy that could delay or stop the progress of the disease.

"The idea that a disturbed immune function contributes to Parkinson's disease is almost one hundred years old," says David Sulzer, of Columbia University, New York. But it is only now that there are concrete indications for such a connection. In damaged brain cells of Parkinson's patients, misfolded molecules of the protein alpha-synuclein are deposited. Fragments of this protein also reach the cell surface, where they are bound by so-called MHC protein complexes and presented to the immune system. "We were able to show that two fragments of the alpha-synuclein can activate T cells involved in autoimmune responses," says Sulzer.

To prove this, he and his colleagues had examined blood samples from 67 Parkinson's patients and 36 healthy subjects. The subjects were between 46 and 83 years old. After contact with 2 of 20 tested alpha-synuclein fragments, only the blood cells of the patients showed strong immune responses. In about one-third of these patients, specific variants of MHC genes were present in the genome, which were only present in 15% of the control subjects. The researchers conclude that in the case of Parkinson's disease, misfolded alpha-synuclein proteins, which can no longer be disposed of by neurons, reach the cell surface. Normally the immune cells on the MHC structures recognize carcinogenic cells that remain undisturbed. However, the immune system reacts to the bound alpha-synuclein as if the cells were infected by a disease-causing agent and had to be eliminated. Therefore, defense reactions are initiated which are directed against such cells.

Now the researchers want to investigate whether these processes only accelerate the death of the neurons and the course of the disease or are of a causal importance. However, the results so far could in any case serve to improve the diagnosis of the disease and identify vulnerable individuals already in the early stages of the disease, says Alessandro Sette of the La Jolla Institute for Allergy and Immunology, a leading member of the research team. First, the findings on other patients should be confirmed and the exact mechanism of the autoimmune reaction analyzed in experiments with cell cultures and animals. "There is the possibility," says Sette, "that immunotherapy can increase the tolerance of the immune system to alpha-synuclein and thus alleviate the symptoms."