Parkinson's Disease : Autoimmunity Could Play Key Role in Neuronal Damage

Abnormal alpha synuclein accumulation in dopamine neurons induces the T-cells to attack and destroy these neurons, thereby contributing to Parkinson’s disease.

Highlights:

Parkinson’s disease is a neurodegenerative disorder that leads to death of dopamine neurons in the brain, with the cause still not clearly established.
Current study suggests that autoimmunity may play a part in the death of dopamine neurons in Parkinson’s disease.

Autoimmune attack of the dopamine neurons could contribute at least in part to Parkinson’s disease (PD), according to a recent study undertaken by scientists at Columbia University Medical Center (CUMC) and the La Jolla Institute for Allergy and Immunology. The study was published today in Nature.

Parkinson’s Disease - Unfolding the Mystery

It has been believed for over a 100 years that a dysfunctional immune system could be one of the factors causing Parkinson’s disease. However, no clear role or probable mechanism has been demonstrated.

Parkinson’s Disease - Causes, Symptoms, Diagnosis, Treatment
Parkinson’s disease is a neurodegenerative disease caused by progressive dopamine brain cells loss. Symptoms of Parkinson’s disease are correctable to an extent.

‘Therapies that suppress the immune response may be potentially useful in preventing neuronal death in Parkinson’s disease.’

Current treatment is mainly symptomatic; with no clear clues as to the cause, the cure for PD still remains elusive.

The findings of the current study suggest that at least 2 fragments of alpha synuclein, an abnormal protein that accumulates in the dopaminergic neurons, could trigger the T cells involved in autoimmune reaction.

"It remains to be seen whether the immune response to alpha-synuclein is an initial cause of Parkinson's, or if it contributes to neuronal death and worsening symptoms after the onset of the disease," said study co-leader Alessandro Sette, Dr. Biol. Sci., professor in the Center for Infectious Disease at La Jolla Institute for Allergy and Immunology in La Jolla, Calif. "These findings, however, could provide a much-needed diagnostic test for Parkinson's disease, and could help us to identify individuals at risk or in the early stages of the disease."

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Possible Role of Abnormal Alpha Synuclein Accumulation – The Study

The study team compared blood samples (containing immune T cells) from 67 Parkinson’s disease patients with 36 age-matched healthy controls not suffering from the disease.
These blood samples were exposed to fragments of alpha synuclein, a protein found in the brain cells to determine whether these fragments stimulated any immune response.
Little or no immune activity was noted in the control blood samples.
In contrast, in the PD patients, a strong immune response was noted against the alpha synuclein fragments as the T cells in these patients had been sensitized to recognize and attack alpha synuclein.
Also, the immune response was associated with the presence of a common gene variant that occurs in the immune system; many PD patients are found to have this gene variant.

The findings of the study suggest that the immune T-cells are tricked into perceiving the damaged dopamine neurons in PD (due to abnormal accumulation of alpha synuclein) as foreign, and attacking them, leading to their death.

"In most cases of Parkinson's, dopamine neurons become filled with structures called Lewy bodies, which are primarily composed of a misfolded form of alpha-synuclein," said Dr. Sulzer. ‘The results raise the possibility that Parkinson’s is partly an autoimmune disease, Dr. Sulzer says, but more research is needed to confirm the idea’.

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Neurons Also Carry Surface Antigens Recognized By the Immune System

Till recently, it was thought that all neurons are protected from immune attack, since they do not carry any antigens on their surface, and thus cannot be recognized by immune T cells.

However, earlier research by Dr. Sulzer and his team has shown that certain neurons including the dopamine neurons, affected in Parkinson’s disease, do carry proteins on their surface that enable their recognition by immune T cells. These neurons are therefore vulnerable to immune attack and death which is what happens in PD.

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Why Abnormal Alpha Synuclein Accumulates In The First Place

With increasing age, the scavenging mechanism of the dopamine neurons fails to get rid of the alpha synuclein, which accumulates and triggers the autoimmune response leading to Parkinson’s disease.

"Young, healthy cells break down and recycle old or damaged proteins," he said. "But that recycling process declines with age and with certain diseases, including Parkinson's. If abnormal alpha-synuclein begins to accumulate, and the immune system hasn't seen it before, the protein could be mistaken as a pathogen that needs to be attacked."

Expanding the Scope of the Current Study

The study team is analyzing these autoimmune responses in more patients. They are working to determine the possible molecular mechanisms involved in the autoimmune response in animal and cellular models to gain more insight into the possible pathogenesis of PD.

"Our findings raise the possibility that an immunotherapy approach could be used to increase the immune system's tolerance for alpha-synuclein, which could help to ameliorate or prevent worsening symptoms in Parkinson's disease patients," said Dr. Sette.Source-Medindia