Neuro-Immune Interactions during Neurodegeneration in Parkinson’s Disease: Role of the Chemokine Network – ParKemoS

To establish the mapping of brain chemokines during Parkinson's disease, we use 1) a mouse model of the disease which is developed by the injection of a neurotoxin that targets specifically the neurons that degenerate in the human disease, 2) cell microdissection technique with a microscope equipped with a powerful laser to quickly recover a few thousand neurons from healthy ou parkinsonian mouse brain 3) a molecular biology approach to measure just a few cells the expression level of chemokines.

The results obtained during the first 18 months of research helped to build a mapping of chemokine expression in the brain a mouse model of Parkinson's disease. Thus, out of 34 chemokines known and studied here, 5 of them seem to be particularly active in the brain of parkinsonian mice. Unexpectedly, none of them is found in diseased neurons. Thus, unlike our initial hypothesis, it seems that these molecules are not involved in the dialogue between neurons and immune cells. By contrast, our results show that these molecules are all produced by local immune cells in the brain as well as by supporting cells called «astrocytes.« Therefore, from these results, we believe that brain chemokines could play a key role in the invasion of brain immune cells circulating in the peripheral blood. Our work over the next 18 months will seek to validate this hypothesis.

If Chemokines can be identified and play a key role in brain inflammation and neuronal death in the mouse model of Parkinson's disease, therapeutic tools could be developed to target their action.

2010: Communication at the10th international congres on Neuroimmunology (Barcelona, Spain). Poster title: Molecular mechanisms of T cell trafficking into the brain in a mouse model of Parkinson's disease.
•2011: 1st ITMO workshop on Neuroimmunology, 20 Mai 2011, Paris, France. Innate and adaptive immunity in Parkinson’s disease. (invited speaker).
•2012: 2nd workshop on Biomarkers in the early diagnosis of neurodegenerative disorders. 7-9 June, 2012, Assisi, Italy. Inflammation and Parkinson’s disease. (invited speaker).
•2012: International PhD program in Neuropharmacology – Summer school of neuroscience. July 7-13, 2012, Catania, Italy. Neuroinflammation in Parkinson’s disease: a target for neuroprotection? (chairman and speaker).

The emerging concept of non-cell autonomous disease mechanisms suggests that neurodegeneration is not just mediated by damages within the affected neurons but is also influenced by interactions with neighboring cells. This so-called neuroinflammatory response produces culprits that could to be at the core of the progressive nature of many neurodegenerative diseases including Parkinson disease. Depicting the mechanism of cell death in Parkinson's disease requires a deeper analysis of these neuro-immune interactions, especially of what are the neuronal damage signals that trigger this neuroinflammatory response. One of the most promising candidates for such cross-talk is the large family of Chemokines which hold potent modulatory effects on immune-cells. Yet, little is known about their cell-type specific expression and regulation under conditions relevant to Parkinson's disease.
Our overall objective is to both characterize and functionally analyze this candidate family as a major neuro-immune modulator in Parkinson's disease. The specific objectives of the project are: (1) to determine the region and cell-type specific expression profile of the Chemokine network during MPTP-induce dopaminergic neurodegeneration in mice and confront results obtained from this experimental model to the real pathology using postmortem human material. (2) to test if the expression or MPTP-induced induction/suppression of a specific candidate chemokine ligand by dopaminergic neurons has a direct effect on triggering/modulating the microglial response in the affected substantia nigra, and thus could have beneficial or detrimental effects on the MPTP-induced dopaminergic neurodegeneration. (3) to assess if MPTP-induced neuron- and/or glial-derived chemokines, locally produced in the affected substantia nigra, could be involved in the brain recruitment of peripheral lymphocyte that, as we have shown, is of detrimental importance for the MPTP-induced dopaminergic neurodegeneration.
Outcomes of this project are double: (1) it should result in a cell-type specific gene expression map of chemokine expression and regulation in dopaminergic neurons and microglia during MPTP-induced neurodegeneration in the SN of mice and provide the basis for a targeted functional analysis of the most promising candidates for their importance as neuro-immune modulators in Parkinson's disease. (2) they have the potential to unravel the role of chemokines as neuron-derived immune regulators in the MPTP-mouse model of Parkinson's disease. It is our hope that insights from this project will allow a better understanding of pathological neuro-immune interactions and might provide novel therapeutic candidates for Parkinson's disease.