海角社区

A team of scientists led by Dr. Michel Desjardins from the University of Montreal and Dr. Heidi McBride from the Montreal Neurological Institute and Hospital (MNI) at 海角社区 have discovered that two genes associated with Parkinson's disease (PD) are key regulators of the immune system, providing direct evidence linking Parkinson's to autoimmune disease.

Using both cellular and mouse models, the team has shown that proteins produced by the two genes, known as PINK1 and Parkin, are required to prevent cells from being detected and attacked by the immune system.

When PINK1 and Parkin are dysfunctional, as is the case in a subset of Parkinson鈥檚 patients, cells display small parts of proteins at their surface, known as antigens, derived from mitochondria. The presence of these antigens at the cell surface causes the activation of immune cells called lymphocyte T cells. These T cells, which can enter the brain, have the ability to destroy any cell displaying the mitochondrial antigens on their surface.

Parkinson鈥檚 is caused by the death of dopamine-producing neurons in the brain. An overactive immune system due to dysfunctional PINK1 and Parkin genes could explain why dopaminergic neurons die in Parkinson鈥檚 patients.

This indicates that Parkinson鈥檚 may be one of many autoimmune diseases, including multiple sclerosis, Type 1 diabetes, rheumatoid arthritis, and lupus. An autoimmune disease is one in which the body鈥檚 own immune system attacks healthy cells.

Researchers suspected that mitochondria, organelles within cells that are responsible for the production of energy and other metabolites, play a role in Parkinson鈥檚. It was widely believed that mitochondria become damaged in Parkinson鈥檚 patients, creating a toxic build-up of broken mitochondria that eventually leads to neuron cell death. However, it has been difficult to provide evidence that this is effectively happening in animal models.

The new findings of the Desjardins/McBride teams linking PD to autoimmune mechanisms, , have been validated in a mouse model of Parkinson's disease where PINK1 or Parkin are absent.

鈥淐linicians have shown that the immune system is activated in the brain of PD patients,鈥� says Dr. Diana Matheoud, a postdoctoral fellow from the University of Montreal and the article鈥檚 first author. 鈥淥ur study explains how an attack by the immune system may be responsible for the destruction of dopaminergic neurons during the disease. We are currently testing whether autoimmune mechanisms lead to the loss of dopaminergic neurons in mice, and developing systems to extend our study to human neurons." 听

鈥淎ntigen presentation was not believed to play a direct role in Parkinson's disease,鈥� says McBride. 鈥淲hile most laboratories are following the trail of the 鈥榯oxic mitochondria鈥� model, our path led us to observe Parkinson's disease from a different point of view. Our approach, centered on the immune system, led us down a different road where we were able to observe that autoimmunity is likely to play an important role in the progression of the disease.鈥�

Now that a link has been established between two key genes involved in the pathology of Parkinson鈥檚 disease and autoimmune mechanisms, the next step is to develop drugs that can limit the presentation of mitochondrial antigens. Remarkably, the mechanism by which mitochondrial antigens are presented involves a process of vesicle formation, originally described by the McBride group, offering molecular targets for the development of new drugs in an effort to block this process.

The researchers鈥� findings may also lead to better treatments for other diseases.

鈥淲e think that our study is paradigm shifting because we have identified a new biological pathway linking mitochondria to immune mechanisms in Parkinson鈥檚 disease. This opens the possibility to use therapies based on modulation of the immune system, something already done for the treatment of other diseases,鈥� says Desjardins. 鈥淚nterestingly, the role played by PINK1 and Parkin in limiting the presentation of mitochondrial antigens may not only regulate a process that impact Parkinson鈥檚 disease, but may also affect other autoimmune diseases like diabetes and lupus, and primary biliary cirrhosis, where a link to mitochondrial antigen presentation has been observed.鈥�

鈥淭his paper suggests an entirely novel mechanism by which these recessive, inherited mutations may lead to neurodegeneration,鈥� says Jon Stoessl, Professor and Head of Neurology at the University of British Columbia & Vancouver Coastal Health, and former Director of the Pacific Parkinson鈥檚 Research Centre. 鈥淭here has been much interest in the potential role of inflammation in PD. Previous studies on Parkin and PINK1 have focused on disruption of mitochondrial housekeeping functions. While the current findings may clearly be related, they suggest an entirely novel approach to the development of targeted therapies. It should be remembered that these are rare causes of Parkinson's disease and the relevance to dominantly inherited and sporadic forms of disease remains to be determined.鈥�

This research was funded with the help of the Canadian Institute for Health Research and the Canadian Research Chairs program of Canada.

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Universit茅 de Montr茅al

Universit茅 de Montr茅al and its two affiliated schools, 脡cole Polytechnique (engineering) and HEC Montr茅al (business) are amongst the world's top 100 universities, according to international rankings. Founded in 1878, the campus today has over听66,000 students and 2,600 professors, making Universit茅 de Montr茅al the second largest university in Canada. Its students are drawn to the university by its deep roots in cosmopolitan Montreal and in consideration of its tenacious dedication to its international mission. umontreal.ca/english

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The Montreal Neurological Institute and Hospital

The Montreal Neurological Institute and Hospital 鈥� The Neuro 鈥� is a world-leading destination for brain research and advanced patient care. Since its founding in 1934 by renowned neurosurgeon Dr. Wilder Penfield, The Neuro has grown to be the largest specialized neuroscience research and clinical center in Canada, and one of the largest in the world. The seamless integration of research, patient care, and training of the world鈥檚 top minds make The Neuro uniquely positioned to have a significant impact on the understanding and treatment of nervous system disorders. The Montreal Neurological Institute is a 海角社区 research and teaching institute. The Montreal Neurological Hospital is part of the Neuroscience Mission of the 海角社区 Health Centre. For more information, please visit听