Nigrostriatal dopaminergic vulnerability in Parkinson's disease: Neuroprotective strategies.

The selective vulnerability of nigrostriatal dopaminergic neurons is a hallmark of Parkinson's disease and underlies its progressive motor decline. These neurons are uniquely susceptible to degeneration due to their extensive axonal arborization, high energy demands, sustained pacemaking activity, and cytosolic dopamine metabolism, which collectively promote oxidative stress and mitochondrial dysfunction. Advances in single-nucleus RNA sequencing and spatial transcriptomics have revealed transcriptionally distinct dopaminergic subtypes within the human substantia nigra pars compacta, such as AGTR1 + /SOX6 + and RIT2 + populations, which exhibit subtype-specific transcriptional stress signatures and are preferentially lost in Parkinson's disease. These findings underscore the role of intrinsic vulnerability, influenced by genetic risk loci, mitochondrial stress, and protein misfolding pathways, including α-synuclein aggregation. Furthermore, neuroinflammation, iron accumulation, and vascular dysfunction act synergistically to amplify neuronal loss. This review integrates molecular, cellular, and systems-level mechanisms contributing to dopaminergic degeneration and evaluates emerging neuroprotective strategies. These include anti-oxidative, anti-inflammatory, mitochondrial therapies, novel biomarkers, gene editing, and cell replacement techniques. Understanding the selective vulnerability of nigrostriatal subtypes offers a promising path toward precision-targeted, disease-modifying treatments for Parkinson's disease.