Periodic Reporting for period 2 - FUELING-TRANSPORT (Deciphering the Role of Huntingtin in Energy Supply for Axonal Transport in Health and Huntington’s Disease)
Okres sprawozdawczy: 2021-07-01 do 2022-12-31
What is the problem/issue being addressed?
Communication within brain cells is essential for brain function allowing cognitive, psychiatric and motor abilities in humans. Such communication depends, at least in part, on the transport of molecules over long distances within brain cells. Indeed, these cells, also known as neurons, contains extensions, called axons that allow them to connect to other brain cells and communicate. Consequently, the transport in axons is highly regulated, requires energy to fuel it and, importantly, it has been found altered in several neurodegenerative disease, including Huntington disease (HD).
In particular, we have shown that the axonal transport of a trophic factor essential for brain communication and survival is altered in HD. In this research program, we hypothesized that the protein that when mutated causes HD plays a role in facilitating the transport of this factor by coupling energy production to energy consumption. Our research aims at the better understanding of this energy machinery with the final objective of restoring such machinery in disease.
Why is it important for society?
Brain pathologies and neurodegenerative disorders are a major health concern for developed countries, with a strong impact on the quality of life of patients and their families. At the European level, brain pathologies represent a burden of about 387 billion euros/year. Among neurodegenerative disorders, HD results in profound and prolonged morbidity requiring institutionalized care and a dramatic economic burden. This work will significantly expand our knowledge on HTT function and dysfunction in HD. There is currently no treatment to slow down or halt the progression of neuronal dysfunction and degeneration in HD. The development of such therapies will inevitably be based on a sound understanding of the etiology of this fatal disease.
Our proposal will decipher the mechanisms key for maintaining the neuronal communication and synapse function within the brain and participant in the pathogenic mechanisms in HD. This may lead to the identification of new therapeutic strategies. Finally, our work is likely to open new perspectives for other neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, which are also characterized by transport defects and energy failure.
Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far
We are currently developing approaches to stimulate energy production on these cellular machineries, ie: vesicles that transport these essential surviving factors. We are currently studying the consequences of the activation of the energy producing machineries on the efficacy of intracellular transport both in vitro and in vivo and their consequences on brain communication and on the capacity to protect neurons from neurodegeneration.
Communication within brain cells is essential for brain function allowing cognitive, psychiatric and motor abilities in humans. Such communication depends, at least in part, on the transport of molecules over long distances within brain cells. Indeed, these cells, also known as neurons, contains extensions, called axons that allow them to connect to other brain cells and communicate. Consequently, the transport in axons is highly regulated, requires energy to fuel it and, importantly, it has been found altered in several neurodegenerative disease, including Huntington disease (HD).
In particular, we have shown that the axonal transport of a trophic factor essential for brain communication and survival is altered in HD. In this research program, we hypothesized that the protein that when mutated causes HD plays a role in facilitating the transport of this factor by coupling energy production to energy consumption. Our research aims at the better understanding of this energy machinery with the final objective of restoring such machinery in disease.
Why is it important for society?
Brain pathologies and neurodegenerative disorders are a major health concern for developed countries, with a strong impact on the quality of life of patients and their families. At the European level, brain pathologies represent a burden of about 387 billion euros/year. Among neurodegenerative disorders, HD results in profound and prolonged morbidity requiring institutionalized care and a dramatic economic burden. This work will significantly expand our knowledge on HTT function and dysfunction in HD. There is currently no treatment to slow down or halt the progression of neuronal dysfunction and degeneration in HD. The development of such therapies will inevitably be based on a sound understanding of the etiology of this fatal disease.
Our proposal will decipher the mechanisms key for maintaining the neuronal communication and synapse function within the brain and participant in the pathogenic mechanisms in HD. This may lead to the identification of new therapeutic strategies. Finally, our work is likely to open new perspectives for other neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, which are also characterized by transport defects and energy failure.
Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far
We are currently developing approaches to stimulate energy production on these cellular machineries, ie: vesicles that transport these essential surviving factors. We are currently studying the consequences of the activation of the energy producing machineries on the efficacy of intracellular transport both in vitro and in vivo and their consequences on brain communication and on the capacity to protect neurons from neurodegeneration.
We are currently developing approaches to stimulate energy production on these cellular machineries, ie: vesicles that transport these essential surviving factors. We are currently studying the consequences of the activation of the energy producing machineries on the efficacy of intracellular transport both in vitro and in vivo and their consequences on brain communication and on the capacity to protect neurons from neurodegeneration.
When investigating the molecular machineries present on vesicles, we discovered that not only these vesicles contain an energy-producing facility that allow them to self propel, but these vesicles also contain a cellular machinery that allow them to sense the environment and follow precise directions within the cells. We propose that in cells, the small vesicles that transport molecules and surviving factors carry not only their own fuel, but their own navigational system.