The conundrum of alpha-synuclein antibody failures in Parkinson's disease: a narrative review of mechanisms and alternative metabolic hypotheses.

Parkinson's disease (PD) remains the second most common neurodegenerative disorder globally, yet disease-modifying therapies remain elusive. The past decade of therapeutic development has been dominated by the hypothesis that alpha-synuclein aggregates spread in a prion-like manner. This catalysed the development of immunotherapy approaches targeting extracellular alpha-synuclein. However, high-profile Phase II and III clinical trials, such as those for cinpanemab and prasinezumab, failed to demonstrate clinical efficacy. This narrative review evaluates alpha-synuclein-targeted immunotherapies, their mechanistic rationale, the underlying reasons for recent clinical trial failures and to propose alternative metabolic frameworks. A literature search of peer-reviewed articles published up to 10 December 2025 was performed using the PubMed database to evaluate immunotherapies, mechanistic models and trial failures in PD. The prevailing 'prion-like' spread hypothesis may be overemphasised in the context of human disease. We propose the 'Single-Neuron Degeneration Hypothesis', suggesting that PD pathology is primarily driven by intracellular autotoxicity - specifically involving the dopamine metabolite aminochrome, mitochondrial dysfunction and oxidative stress - occurring independently within each dopaminergic neuron. Multifactorial contributors to trial failure include the inadequacy of preclinical models such as MPTP, the insensitivity of the MDS-UPDRS, diagnostic heterogeneity and the statistical reality of neuronal loss rates. Future therapeutic strategies must integrate intracellular neuroprotection alongside extracellular clearance approaches, with significantly earlier intervention.