Abstract Purpose of Review To critically synthesize proposed mechanisms underlying idiopathic neurodegeneration of substantia nigra (SN) neurons, emphasizing age-related vulnerability and neuron-specific physiological and biochemical characteristics. Recent Findings We use inclusion (IN) and exclusion (EX) criteria. IN criteria (for the databases PubMed, Google Scholar, Scopus, and Cochrane, using the keywords “neurodegeneration AND substantia nigra,” “neuroinflammation AND substantia nigra,” “neurotoxic molecules AND neurodegeneration,” “activated microglia AND neuronal death,” “Parkinson disease,” and “problems OR unresolved problems OR questions AND Parkinson disease”): randomized controlled trials (RCTs), cohort studies, systematic reviews and meta-analyses, and experimental studies in vivo/in vitro. The timeframe is 2000–2025, and the language is English only. Only peer-reviewed journal articles with full text availability are included. EX criteria: articles that do not match PICO/PECO criteria, exist only in textbooks without proper approval, do not repeat studies, or have a very small sample size with no appropriate justification, or have a clear conflict of interest. AGREE II and AMSTAR tests were consolidated with three co-authors. Five primary hypotheses were identified to explain the pathogenesis of SN neurodegeneration: (1) dysfunction of the ubiquitin-proteasome system; (2) imbalance in cellular micro- and macronutrients, including iron dysregulation and ferritin accumulation; (3) involvement of neuropigments (neuromelanin and lipofuscin) in neuroinflammatory processes; (4) humoral neurotoxicity mediated by glutamate, dopamine, and metabolic byproducts; and (5) microglial activation and immune system engagement. These mechanisms were evaluated in the context of clinical observations, biochemical and physiological processes, and current treatment strategies. Economic and social impacts of neurodegenerative conditions were also assessed. Summary The heterogeneity of SN neurons, their embryonic connectivity to both midbrain and prosomeric basal regions (P1–3), and the dual roles of neurotransmitters and neuropigments underscore the complexity of SN pathophysiology. Observed asymmetries in neurodegeneration, particularly in Parkinson’s disease, may reflect structural organization, differential innervation, and immuno-humoral regulation. Unlike previous studies addressing only general aspects of neurodegeneration, this analysis integrates cellular, molecular, and physiological perspectives, emphasizing mechanisms such as ferritin-mediated neurocytolysis, glial activation, and neurotransmitter toxicity. These insights advance understanding of SN neurodegeneration and may inform future therapeutic strategies.
Nikolenko et al. (Fri,) studied this question.