Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - IFNBetaMito (Role of IFN-β in mitochondrial homeostasis and impact on Parkinson Disease)

Teaser

Parkinson Disease (PD) is the second most common neurodegenerative disorder of the central nervous system (CNS) affecting the motor system and progressing to dementia in most patients. It affects approximately 1.2 million people only in Europe. The cost for society was...

Summary

Parkinson Disease (PD) is the second most common neurodegenerative disorder of the central nervous system (CNS) affecting the motor system and progressing to dementia in most patients. It affects approximately 1.2 million people only in Europe. The cost for society was estimated to be over 13 billions euros in 2010, and is increasing each year with the aging of the European population. Currently there is no cure for the disease. Therefore it is essential to obtain a better knowledge of the molecular mechanism involved in PD to develop new therapeutics and screening strategy. One of the major pathological changes could be mitochondrial functions, the powerhouse in neurons, which is reported to be associated not only with PD but also with Alzheimer’s disease. In our project we investigated the role of IFNβ in regulating neuronal mitochondrial homeostasis.
IFNβ is a cytokine that reduces the inflammatory response in the brain, and is being used to treat patients with multiple sclerosis (MS), a neuroinflammatory disease of the CNS caused by immune cells. Previously, the host laboratory has reported that mice lacking IFNβ are more susceptible to experimental autoimmune encephalomyelitis (EAE), a mice model for MS, which was accompanied by enhanced neuroinflammation and demyelination. The host laboratory has recently discovered that the Ifnb–/– mice displayed age-related motor and cognitive deficits, which were correlated with reduced neurite extensions, elevated aggregated α-synuclein, Lewy body formation, and spontaneous neurodegeneration, resembling the clinical features of PD with dementia. In this study, IFNβ deletion caused a late-stage block in the autophagy pathway, which caused α-synuclein aggregation and Lewy body formation. However, the specific molecular mechanisms associating IFNβ to neuroprotection remained to be identified.
Although animal models of PD have provided essential knowledge to the pathologies, none of these models recapitulate both the progressive neurodegeneration, protein aggregation and dementia seen in PD patients. The current available models are mainly modelling small percentage of familial form of disease, while the pathology and clinical manifestation in Ifnb–/– mice, to a much higher degree resembles sporadic PD with dementia, thus constitutes a valuable and novel model for studying the basic molecular mechanisms of these sporadic diseases which encompass more than 95% of patients.
Mitochondria are cell organelles that generate most of the energy supply of the cells. They are also involved in a number of additional functions such as cell signalling, differentiation or cell death. They are highly dynamic organelles that can fuse, divide or migrate to respond to metabolic or environmental changes. Familial forms of PD is also reported to be associated with genes in mitochondrial homeostasis, such as pink1, parkin or park7, and we hypothesized that mitochondrial homeostasis might be altered in Ifnb-/- mice, in particular mitophagy, fusion/fission, and mt-DNA maintenance which are essential altered mechanisms seen in PD. Regulation of the IFNβ pathway could be used therapeutically against PD, thus to understand its potential action on mitochondria is essential. To pursue this, our specific objectives were to:
Objective 1: Characterize the mitochondrial alterations in Ifnb–/– neurons
Objective 2: Identify the mitochondrial molecular mechanisms regulated by IFNβ
Objective 3: Elucidate the impact of IFNβ treatment on restoring mitochondrial function in PD-models in vivo

Work performed

1/ We reconstituted the morphology of mitochondria in primary neurons but also, in brain tissue from Ifnb+/+ and Ifnb-/- mice, using the cutting edge technology of serial-block face electron-microscopy. We analysed mitochondrial functions, such as ATP synthesis and ROS production.
2/ Using microscopy-based approaches, immunoblotting and genetic alterations such as CRISPR/Cas9, we discovered the molecular mechanisms implicating an important role for IFNβ in mitochondrial homeostasis. Finally, we identified some pathological features found in Ifnb-/- mice that are linked to defect in mitochondrial homeostasis. These pathological features were replicated in vivo on the behaviour and motor capacities of the mice, showing an impact on neurodegeneration.
3/ Finally, we developed mitochondrial transfer in vivo, in the brain and observed the positive impact of such a therapy on the cognitive and motor capacities on Ifnb-/- mice.
Our results strongly demonstrate that IFNβ is a neuroprotective cytokine, notably by regulating mitochondrial homeostasis and suggest IFNβ and/or downstream pathways as targets for treatment of PD. Additionally, we developed a new therapeutic approach for PD patients.
4/ Exploitation and dissemination: results have been disseminated to 3 international conferences and 2 national conferences. Additionally, 2 manuscripts (1 submitted, 1 in preparation) should be published.

Final results

IFNβ has been described previously as a neuroprotective cytokine, in the context of immune cells during infections, in which its role has been extensively studied. However, a role in the basic homeostasis of neurons is a completely new concept which open the door to a complete reinterpretation of data for scientists working in the field of neurobiology, and could be extended to other tissues, such as muscles and bones.
The discovery of the role of IFNβ in mitochondrial homeostasis will influence the approach to treat and screen patients with neurodegeneration as it involves 1/potential impact of infections on the CNS, leading to development of neurodegenerative disease 2/ different approach of the role of IFNβ in MS 3/new screening strategy for PD and potentially other neurodegenerative diseases 4/ new therapeutic strategies for PD and potentially other neurodegenerative diseases. More importantly, the development of mitochondrial treatment is an interesting new therapeutic concept that we expect to be developed in the near future.