Caractérisation de la régulation de TFEB par AMPK pour un nouveau traitement potentiel de maladies neurodégénératives


Mathieu Paquette

Université McGill


Domaine : viellissement

Programme : Formation de doctorat

Concours 2017-2018


Parkinson Québec

Neurodegenerative diseases and dementias such as Alzheimer's and Parkinson's are afflicting more than 500000 Canadians and 35.6 million person worldwide. These numbers are estimated to rise to 65.7 million and to 115.4 million affected individuals worldwide in 2030 and 2050, respectively. It is afflicting more people than breast and prostate cancer combined. The need for new medicine is major, since current treatments are only able help the cognitive and behavioral symptoms. These diseases are characterized by the accumulation of naturally produced toxic proteins, and this is correlated with a reduction in our cell's recycling machinery function as we are aging. Recently, a new master regulator of protein recycling has been identified, called TFEB.

However, nobody knows completely how it is controlled in our cells. Our preliminary results have identified a new player, easily modulated by drugs, named AMPK. This protein might control TFEB and thus, activate the recycling machinery. We are proposing to further investigate the molecular interactions between the two, and then to explore their therapeutic potential. We will first understand how the recycling machinery is regulated molecularly and this will give us a better understanding of these diseases. We will then use a worm model of Alzheimer's and Parkinson's disease. Using already approved drugs targeting our new players, we will try to reduce the paralysis occurring in worms. Upon positive results, we will use these drugs on various mice models.

We are expecting to see a decrease in the accumulation of toxic proteins and an improved survival. It will give us a better understanding of the diseases progression and of the molecular mechanism controlling our normal cell metabolism and homeostasis. This project has the potential of significantly improve the outcomes of many neurodegenerative diseases.