Functional dissection of the piRNA pathway in adult neurogenesis and neuroinflammation

Piwi proteins and the small non-coding RNAs interacting with them (piRNAs), collectively referred to as the piRNA pathway, are best known in gonads where they safeguard genomic integrity and male fertility. The piRNA pathway is also present in various somatic tissues, especially in the central nervous system (CNS), and altered piRNAs expression has been implicated in pathological and inflammatory conditions such as neurodegenerative diseases. However, little is known about the underlying mechanisms, and the potential functions of PIWI-piRNAs in brain cells remain unclear. This thesis extends our prior research presenting the initial evidence of the functional role of piRNA pathway in neurogenesis and neuroinflammation, which are critical processes for maintaining central nervous system (CNS) homeostasis and cognitive function. Piwil2 and piRNAs were discovered in adult neural progenitor cells (aNPCs) to support neurogenesis by reducing cellular senescence and neuroinflammation. In this thesis, a constitutive Mili knockout mouse model was used to validate and expand these findings. In vivo proliferation disturbances and in vitro impaired differentiation of aNPCs with mutated Mili were observed. Concerning neuroinflammation, our investigation demonstrated that Piwil2 depletion in the postnatal hippocampus leads to the generation of reactive astrocytes. This thesis extends these findings by illustrating that Mili knockdown results in microgliosis. Additionally, the presence of the piRNA pathway was uncovered in microglia. Microglial Piwil2 and piRNAs were shown to be responsive to both acute (LPS-induced) and chronic (inflammaging) inflammation. Moreover, inflammation-responsive piRNAs are Mili-dependent and are predicted to target, and therefore potentially regulate, several gene transcripts involved in inflammatory processes. The work reported in this thesis provides an initial characterization of the piRNA pathway's role in adult neurogenesis and neuroinflammation, suggesting a broader function of the piRNA pathway as a guardian of brain homeostasis. This offers potential therapeutic avenues for age-related central nervous system (CNS) disorders, contributing to the promotion of successful brain aging.