Mitochondria-Derived Extracellular Vesicles in Friedreich s Ataxia
Abstract
Friedreich’s ataxia (FA) is a rare neurodegenerative disease characterized by mitochondrial dysfunction caused by deficiency of the mitochondrial protein frataxin (FXN). Low amount of FXN leads to accumulation of iron within mitochondria, which are the powerhouse of the cells. Patients affected by FA display loss of neurons and inflammation in the spinal cord, cerebellum, and peripheral nerves, and this leads to neurological manifestations and motor disability. To date, no cure exists for FA, and the cause of neuronal death and inflammation are still obscure. When mitochondrial are damaged, they can be removed inside the cell by a process called mitophagy. An alternate way to eliminate damaged mitochondria in physiological conditions is their ejection outside the cell via the so-called mitochondrial extracellular vesicles (mitoEVs) that can be removed by specialized cells of the immune system by phagocytosis. In the brain, the predominant phagocytic cells are microglia that eliminate microbes, dead cells, and other particulate that may endanger neurons. In this project, we want to test whether in FA there is an abnormal release of mitoEVs and an impaired or aberrant phagocytic and inflammatory response of microglia. To this end, we will use mouse models of FA affected by mild and severe form of the disease. In the first phase of the research, we will characterize mitoEVs of cerebellum and cultured cerebellar neurons in terms of morphology, abundance, and cargo to highlight possible differences between healthy and FA affected mice. Microglia differences will be also investigated through high-throughput techniques. Next, we will carry out a series of in vitro experiments on neurons and microglia cells isolated from cerebellum to test whether in FA the communication between such cell types is altered due to the presence of abnormal mitoEVs in terms of abundancy or cargo and this could be responsible for the setting of an inflammatory phenotype of microglia. As mitoEVs can spread in circulating fluids, we will also search for cerebellum-derived mitoEVs in plasma and cerebrospinal fluid to test whether their abundancy could reflect the stage of the disease. Performing this research, we will hopefully lay the foundation for future studies not only for expanding our knowledge on the implication of mitoEVs in the neurodegeneration but also for suggesting cerebellar-derived mitoEVs as low-invasive biomarkers for assessing FA progression and response to therapy in preclinical models.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310005
Entities
People
- Katia Aquilano
Organizations
- Sapienza University of Rome
- United States Army