A Spatially Resolved View on the Aging Substantia nigra: An Exploratory Proteomic Study

Physiological aging is accompanied by structural and molecular changes in the brain, with varying degrees in different brain areas, and is considered one of the major risk factors for neurodegenerative diseases. Thus, the present study focuses on elucidating age-related changes in the substantia nigra pars compacta (SNpc), a brain region particularly vulnerable in Parkinson's disease. Here, the aim is to gain a spatially resolved view of aging-dependent alterations to conclude early processes potentially involved in neurodegeneration. Neuromelanin granules and SNpc tissue are isolated from tissue samples of young and elderly individuals via laser microdissection and measured by mass spectrometry to ascertain changes in protein expression in response to age. The findings include the identification of reduced levels of proteins involved in dopaminergic neurotransmission, either suggesting a specific loss of dopaminergic neurons or a reduction in metabolic activity. Furthermore, increased neuroinflammation is observed in elderly individuals and alterations in vesicular trafficking as well as mitochondrial proteins. Consequently, this exploratory study suggests that alterations causing known pathomechanisms of Parkinson's disease are already occurring in the physiological aging process. Since aging is still the most important risk factor for neurodegenerative diseases, these findings strengthen the necessity for studying age-related changes.