Twenty-five years of progress in Parkinson’s disease research: from dopamine replacement to biological definition and regenerative therapy

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The first quarter of the twenty-first century has transformed Parkinson’s disease (PD) from a predominantly motor, dopamine-deficiency syndrome into a heterogeneous multisystem disorder defined across clinical, genetic and molecular dimensions. This overview follows the trajectory of these advances from the historical foundations established prior 2000 to present concepts of prodromal disease, progression, biological classification and precision medicine. Epidemiological work has established PD as the fastest-growing major neurological disorder, while systematic characterization of non-motor symptoms has shifted diagnosis and attention beyond the nigrostriatal system in PD research. Imaging has progressed from exclusionary structural magnetic resonance imaging (MRI) to quantitative susceptibility, diffusion and molecular approaches, although no single imaging biomarker yet provides a stand-alone diagnosis of PD. The discovery of α-synuclein gene mutations and its presence as protein in Lewy bodies and neurites connected genetics, protein aggregation and selective neuronal vulnerability. Seed amplification assays (SAA) now enable robust detection of pathological α-synuclein in cerebrospinal fluid and have catalysed biologically anchored staging proposals. At the same time, negative phase 2 antibody against α-synuclein trials illustrate the challenges of target engagement, disease heterogeneity and intervention timing. Genetics and cell biology have placed lysosomal proteostasis, in particular glucocerebrosidase 1 (GBA1) dependent pathways, at the center of disease-modification strategies. Dopaminergic therapy remains extraordinarily effective symptomatically, with continuous delivery systems extending its utility for intermediate and late stages of the disease, whereas cell replacement has re-entered clinical development through standardized pluripotent-stem-cell-derived midbrain dopaminergic progenitors. The next phase of PD research will depend less on a single unifying mechanism than on integrating molecular state, the pattern of neuronal injury, clinical phenotype and individual trajectory to select the right intervention at the right biological stage.