At the nucleus of neuronal health: Drosophila insights into LaminB-dependent homeostasis in aging and cell death

Brain neurons play a crucial role to maintain organism health in response to macro/micro-environmental biophysical and biochemical cues, and their dysfunction and death drive aging and diseases. However, cellular mechanisms controlling neuronal health are incompletely understood. Drosophila has proven a paramount model to understand fundamental pathways of tissue development, homeostasis, and cell death in health and disease. Among these pathways, the regulation of nuclear structure and function, including genome organization, RNA synthesis and processing, DNA damage repair, and nucleocytoplasmic transport, has been shown to play a major role. In this regulation, the nucleoskeleton, a meshwork of type A/C and B Lamin proteins, provides an interface between the cytoskeleton and chromatin, controlling (epi)genome dynamics and nucleocytoplasmic compartmentalization, also by interacting with the inner nuclear membrane and pore complexes. In postmitotic neurons, LaminB is the major nucleoskeletal component. In this Review, I focus on the key role of nuclear LaminB dynamics in neuronal homeostasis in aging and cell death, highlighting the power of Drosophila models to uncover the underlying fundamental mechanisms. In this context, I spotlight that the regulation of nuclear LaminB structure and function is emerging as a stress-integration gatekeeper controlling neuronal response to macro/micro-environmental biophysical and biochemical cues, which maintains neuronal health, and whose impairment drives neuronal aging and non-apoptotic cell death in neurodegenerative diseases.