Nuclear dysfunction in aging and neurodegeneration

Neurodegenerative diseases are characterized by a loss of neuronal function and structure, often in a region-specific manner. Multiple factors contribute to neuronal dysfunction and death, including pathogenic protein buildup, protein mislocalization, and inflammation. Despite extensive research, the common mechanisms driving neurodegeneration remain incompletely understood, partly because pathological processes affect interconnected cellular components such as the cytosol, cytoskeleton, and nucleus. Emerging evidence indicates that changes in nuclear structure and function are not simply secondary to cellular stress but play key roles in aging and neurodegenerative disease progression. This review explores important aspects of nuclear dysfunction, including alterations in nuclear architecture, chromatin organization, nucleocytoplasmic transport, DNA damage responses, and inflammatory signaling. It further discusses how these processes converge to increase neuronal vulnerability and may extend beyond normal aging to promote neurodegeneration. Overall, this review highlights nuclear dysfunction as a significant factor in neuronal impairment and underscores the need for therapies targeting nuclear integrity.