The role of granulins in regulating adult zebrafish brain homeostasis and regeneration

Zambusi, Alessandro (2021): The role of granulins in regulating adult zebrafish brain homeostasis and regeneration. Dissertation, LMU München: Graduate School of Systemic Neurosciences (GSN)

Abstract

Reduced neuronal functionality and poor neuronal recovery are among the most detrimental outcomes in aging individuals and patients with neurodegenerative diseases and/or traumatic brain injuries. Therapeutic interventions face the major problems of effectively enhancing the generation of new neurons and limiting the secondary tissue damage in the CNS. The presence of long-lasting glial scar and chronic neuroinflammation hinders the survival and proper integration of the limited pool of new neurons in the pre-existing circuitry of the mammalian CNS. In contrast to mammals, zebrafish possess numerous active stem cell niches during adulthood as constant source of neurogenesis and display extensive regenerative capacity in the CNS. The high regenerative potential correlate with the ability to inactivate the immune response in a timely manner, thus avoiding the long-lasting neuroinflammation observed in mammals. For these reasons, understanding the cellular and molecular mechanisms underlying the neurogenic potential and the regenerative capacity in the injured CNS of zebrafish may play a pivotal role in the development of new therapeutic approaches aimed to ameliorate the quality of life of aging individuals and patients with neurodegenerative diseases and/or with CNS injuries. To this goal, I first validated the relevance of zebrafish as model to study the development and progression of established age-associated hallmarks, including reduced neurogenesis, exacerbated neuroinflammation and telomere shortening. Furthermore, I demonstrated the role of granulins in regulating the aging kinetics of the adult zebrafish CNS. Granulin-deficient zebrafish showed premature aging in the brain, displaying typical age-related hallmarks already during young adulthood. Moreover, I extensively studied the regenerative response to a mild model of traumatic brain injury and characterized the activation and de-activation of microglial cells during the regenerative time course. I identified an injury-induced pro-regenerative microglial population that is initially beneficial for regeneration but needs to be inactivated in a timely manner to prevent long-lasting neuroinflammation and tissue scarring. The pro-regenerative microglial population was characterized by accumulation of lipid droplets and phase-separated TDP-43 that were promptly cleared to complete regeneration. Furthermore, I demonstrated that granulins play a pivotal role in the regulation of microglial de-activation, promoting the clearance of lipid droplets and phase separated TDP-43 in microglial cells, subsequently stimulating their transition back to homeostasis. The translational value of my research is strengthened by the presence of enhanced microglial reactivity associated with lipid droplets and TDP-43 condensates in human patients with stroke. Altogether, the core data I present in this thesis identified granulins as key regulators of aging kinetics and regeneration in the adult zebrafish CNS, making them valuable targets for the development of new therapeutic applications aimed to ameliorate age-associated hallmarks and pathological outcomes caused by traumatic brain injuries in human patients.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Themengebiete: 500 Naturwissenschaften und Mathematik ; 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie
• Fakultäten: Graduate School of Systemic Neurosciences (GSN)
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 16. Dezember 2021
• 1. Bericht­erstatter:in: Ninkovic, Jovica