Dysregulation of the Extracellular Matrix in the Synaptic Pathology of Parkinson’s Disease: Molecular Mechanisms and Novel Therapeutic Approaches

Parkinson’s disease (PD) is defined by the progressive degeneration of dopaminergic neurons within the substantia nigra and the pathological accumulation of α-synuclein (α-syn) aggregates. Beyond these intracellular hallmarks, the extracellular matrix (ECM) has emerged as an active regulator of synaptic dysfunction, neuroinflammation, and disease progression. Recent multi-omics evidence, including transcriptomic and proteomic profiling of post-mortem tissue and iPSC-derived neurons, demonstrates consistent dysregulation of ECM components across both sporadic and genetic PD subtypes—typified by downregulation of basement membrane collagens (COL4A) and integrin signaling (ITGB1), alongside upregulation of matrix metalloproteinases (MMPs). These alterations destabilize perineuronal nets (PNNs), allow prion-like α-syn propagation, and promote glial activation through TLR-mediated signaling. Circulating ECM-derived neoepitopes (C1M, C4M) may complement neurofilament light chain as prognostic biomarkers of disease progression, although prospective validation remains necessary. Pharmacological strategies targeting MMP activity (e.g., doxycycline), integrin–FAK signaling (ATN-161), and MMP–TIMP balance (mesenchymal stem cells) represent emerging therapeutic avenues, though clinical evidence in PD remains limited. This review synthesizes current evidence on ECM dysregulation in PD and discusses its implications for biomarker development and disease-modifying intervention.