Year of selection 2016
Institution Neurosciences Division Institute of Molecular Biology and Biotechnology
With age, brain functions progressively deteriorate, potentially paving the way for neurodegenerative disorders such as Alzheimer's or Parkinson's disease. What mechanisms are responsible for the detrimental effects of ageing on neuronal cells? Despite it being a universal phenomenon, the cellular and molecular underpinnings that govern age-related deterioration of the nervous system remain obscure. It is increasingly appreciated that deregulation in the activity of cellular organelles called mitochondria – key energy suppliers of the cell –, plays a key role in the onset of age-related neural dysfunction. To shed light on this fundamental issue, Dr. Konstantinos Palikaras specifically aims to investigate how ageing and stress conditions affect the standard process by which defective mitochondria are eliminated from the cell to maintain proper cellular functions. In doing so, his objective is to provide unprecedented insight into the underpinning mechanisms that drive brain ageing, potentially opening the door for new therapeutic approaches for dementia or other age-associated diseases.
"Elimination of impaired mitochondria is essential in long-lived, highly metabolically active cells, including neurons", explains Dr. Konstantinos Palikaras. "The accumulation of damaged mitochondria leads to cellular dysfunction and eventually to death". To keep a healthy pool of mitochondria, the cell uses a selective degradation process called mitochondrial autophagy (mitophagy), which targets the defective organelles for destruction, the equivalent of the 'kiss of death' for unhealthy mitochondria. "Recent findings implicate mitochondrial abnormalities in the pathogenesis of neurodegenerative diseases, notably highlighting inadequate autophagy as a contributing factor", highlights Dr. Konstantinos Palikaras. "But many questions remain unanswered about the molecular mechanisms that modulate mitophagy, especially in neuronal cells". The project aims to fill the gap by further investigating the role of mitophagy in different types of neurons, looking specifically at what molecular components play a role in the regulation of mitochondrial fate and how these mechanisms are affected by age.
Elucidating neuronal ageing using a powerful worm model
To conduct his research, Dr. Konstantinos Palikaras is using a highly malleable genetic model organism, the worm Caenorhabditis elegans. Being one of the simplest organisms with a nervous system, the short-lived transparent nematode is well-suited to study neuronal mechanisms related to age. Combining this powerful model organism with state of the art imaging technologies, the researcher and his team will be able to monitor mitochondrial activity in vivo – in a living organism –, and decipher the molecular mechanisms at play throughout the course of their lives. Once the molecular processes are dissected, Dr. Konstantinos Palikaras plans to screen and test already approved drugs to find compounds capable of regulating mitophagy. "We will investigate how these compounds affect neuronal function and cell death. The outcome of our research will potentially lead to identification of novel targets for the pharmaceutical industry to develop new drugs", the researcher explains.
With the world's population ageing, degenerative diseases have become a high priority topic for society. Understanding the mechanisms of brain ageing is absolutely crucial to envision new and innovative strategies to improve end-of-life care, find novel therapeutic approaches for degenerative diseases and decrease mortality. In this sense, Dr. Konstantinos Palikaras' project will significantly contribute to unravelling the cellular and molecular basis of age-related brain diseases, a form of disorder for which additional insight is highly needed.