Comprehensive review linking α-synuclein aggregation, mitochondrial dysfunction, oxidative stress, neuroinflammation, and peripheral-central communication to current and emerging PD therapies—covering symptomatic pharmacotherapy, α-syn-targeted immunotherapies, iPSC-based regenerative approaches,…

Synthesizes actionable mechanistic insights and translational therapeutic avenues (immunotherapy, cell replacement, gene therapy), helping researchers prioritize targets, repurposing opportunities, and design of multi-modal, clinically relevant Parkinson’s interventions.

Parkinson's disease (PD) is a neurodegenerative disorder primarily characterized by motor impairments such as bradykinesia, tremor, and rigidity. Its neuropathological hallmarks include the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) and the aggregation of α-synuclein (α-syn) into Lewy bodies (LBs), which gradually spread to other central nervous system regions and peripheral tissues. The etiology of PD is multifactorial, involving a complex interplay of genetic predisposition, aging, environmental exposures, and lifestyle factors. Disease pathogenesis is predominantly driven by the synergistic action of core pathological mechanisms, including α-syn aggregation, oxidative stress (OS), mitochondrial dysfunction, and neuroinflammation. In recent years, the role of peripheral-central communication pathways in disease initiation and propagation has garnered significant attention. To date, pharmacotherapy remains the mainstay for improving the quality of life in PD patients. The most commonly used clinical agents primarily target the replenishment of depleted dopamine in the brain. However, these medications only alleviate symptoms and do not slow disease progression. This inherent limitation underscores the urgent need for more effective therapeutic strategies. This review aims to systematically outline the network of PD pathogenesis and the evolution of its treatment strategies, with a particular emphasis on a holistic perspective from etiology to therapy. It critically evaluates current bottlenecks in drug treatment and provides an in-depth analysis of potential candidate drugs for PD, as well as the latest advances in α-syn-targeted immunotherapies, iPSC-based regenerative therapies, and gene therapies. Building on this foundation, we further argue that the future of PD management must shift towards integrated, multi-target, and personalized therapeutic strategies to overcome existing efficacy barriers.