Role of sirtuin 2 in the brain is cell-type and context-dependent: Implications for therapeutic targeting.

Sirtuin 2, a NAD+-dependent deacetylase of the sirtuin family, has emerged as a pivotal regulator of brain physiology and pathology. Highly expressed in the central nervous system, sirtuin 2 exerts diverse and cell-type-specific functions in neurons, oligodendrocytes, astrocytes, and microglia. This review provides a comprehensive synthesis of current knowledge on sirtuin 2 within the central nervous system, emphasizing its multifaceted roles across different brain cell types and its potential as a therapeutic target in neurological disorders. In neurons, sirtuin 2 modulates axonal dynamics, mitochondrial function, and synaptic plasticity, displaying both neuroprotective and detrimental effects depending on context. In oligodendrocytes, sirtuin 2 is essential for differentiation, myelination, and axonal metabolic support via exosomal transfer, while its dysregulation contributes to hypomyelination and age-related myelin decline. In astrocytes, sirtuin 2 influences metabolism, senescence, and reactive gliosis, exerting protective effects under physiological conditions but potentially aggravating pathology after injury or in Alzheimer's disease. In microglia, sirtuin 2 modulates inflammatory responses, acting as either a suppressor or amplifier of neuroinflammation depending on the stimulus and disease context. The dual, sometimes opposing, functions of sirtuin 2 across central nervous system cell types underscore the complexity of its regulation and the need for context-dependent therapeutic approaches. By integrating evidence from genetic and pharmacological studies, this review delineates the cell-specific mechanisms through which sirtuin 2 influences central nervous system physiology and pathology. Understanding these heterogeneous and context-dependent actions is essential to harness the therapeutic potential of sirtuin 2 modulation in neurodegenerative, inflammatory, and demyelinating diseases.