DOPAL links dopamine dysregulation to neurodegeneration: a translational systematic review and meta-analysis

3,4-Dihydroxyphenylacetaldehyde (DOPAL) is the most reactive dopamine (DA)-derived aldehyde and has been implicated in selective dopaminergic neurodegeneration in α-synucleinopathies, including Parkinson’s disease (PD) and multiple system atrophy (MSA). Here, we present the first comprehensive translational systematic review and meta-analysis examining the role of DOPAL in neurodegenerative diseases across molecular, experimental, and clinical studies. We synthesized evidence from cell-free, in vitro, ex vivo, in vivo, and human studies to evaluate DOPAL as a pathogenic mediator, experimental model, biomarker, and therapeutic target. Cell-free studies consistently linked DOPAL to α-synuclein aggregation, oxidative stress, and mitochondrial dysfunction. In vitro studies demonstrated robust neurotoxicity following DOPAL exposure, while our meta-analysis confirmed a significant dose-dependent reduction in cell viability, supporting its utility as a model of dopaminergic degeneration. Animal studies further established DOPAL-mediated models as reproducing pathological and behavioral features of PD. Clinical and post-mortem evidence demonstrated altered DOPAL levels in PD and MSA, supporting its translational relevance as a potential biomarker. Finally, assessment of reporting quality and risk of bias highlighted methodological strengths but also important limitations across the current literature. Altogether, this work positions DOPAL as a central contributor to dopaminergic neurodegeneration and provides an integrated translational framework for future mechanistic and therapeutic research.