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15 June 2026

21 Pages

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

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Neurophysiology Department, National Institute of Neurology and Neurosurgery, Mexico City 14269, Mexico
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Mexican Faculty of Medicine, La Salle University, Mexico City 14000, Mexico
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Department of Electrical Engineering, Basic Sciences and Engineering Division, Metropolitan Autonomous University, Iztapalapa Campus, Mexico City 09340, Mexico
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Public Health Intelligence Unit, National Institute of Public Health, Cuernavaca 62100, Mexico
Life2026, 16(6), 1007;https://doi.org/10.3390/life16061007
This article belongs to the Special Issue New Insights into Parkinson’s Disease: From Molecular Basis to Therapy—2nd Edition
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Abstract

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.

1. Introduction

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder worldwide, affecting over 10 million individuals, a figure expected to rise with global population aging [1,2,3]. Clinically, PD is defined by the progressive degeneration of dopaminergic neurons in the Substantia Nigra pars compacta (SNpc) and dysfunction of the nigrostriatal pathway, resulting in cardinal motor manifestations such as bradykinesia, rigidity, and resting tremor, alongside diverse non-motor symptoms [4,5,6,7]. The pathological hallmark of PD is the abnormal accumulation of alpha-synuclein (α-syn) within Lewy bodies and Lewy neurites [8]. Chronic neuroinflammatory cascades mediated by microglia and astrocytes also contribute to early synaptic dysfunction and disease progression [9]. Research on PD pathogenesis has traditionally focused on intracellular mechanisms, including mitochondrial dysfunction, oxidative stress, and impaired protein degradation through the ubiquitin–proteasome system and autophagy [10]. Although these studies have clarified key aspects of PD biology, they do not fully explain the clinical heterogeneity or the early synaptic alterations that precede neuronal loss [11,12,13]. More recent work suggests that trans-neuronal propagation of misfolded α-syn aggregates is central to disease progression [14,15,16]. Within this framework, the extracellular matrix (ECM) of the central nervous system (CNS) has gained attention as a dynamic regulator of neuronal connectivity, synaptic stability, and neuroinflammatory signaling [17,18].
The neural ECM is a structurally organized and functionally diverse network composed of collagens, laminins, glycoproteins, and chondroitin sulfate proteoglycans, which regulate cell adhesion, integrin signaling, and the spatial compartmentalization of synaptic microdomains [19,20,21]. Under physiological conditions, these constituents support the assembly of perineuronal nets (PNNs) that stabilize mature neural circuits and modulate activity-dependent synaptic plasticity [22]. ECM structural integrity also acts as a barrier against the intercellular dissemination of aggregated proteins such as α-syn [23]. This barrier function relies on at least three complementary mechanisms: (i) the dense meshwork of chondroitin sulfate proteoglycans and hyaluronan sterically hinders the diffusion of large oligomeric species [22,24]; (ii) perineuronal nets enwrap specific neuronal populations and limit the lateral mobility of membrane-associated aggregates [22]; and (iii) ECM components such as laminin and collagen IV bind directly to cell-surface receptors (e.g., integrins, dystroglycan), sequestering extracellular α-syn and reducing its availability for uptake by neighboring cells [19,20]. Consequently, degradation of these structures by MMPs removes physical restraint on prion-like propagation.
Recent multi-omics studies integrating transcriptomic and proteomic analyses of post-mortem brain tissue, experimental models, and patient-derived induced pluripotent stem cell (iPSC) neurons have shown widespread dysregulation of ECM components in both genetic and sporadic forms of PD [24,25,26,27,28,29,30]. A recent systematic review of ECM-related transcriptional and proteomic alterations in PD [30] provides a synthesis of these observations, which the present narrative review extends by integrating mechanistic, biomarker, and therapeutic dimensions. These studies frequently report downregulation of structural collagens and integrin subunits together with upregulation of matrix metalloproteinases [31]. ECM disruption alters synaptic signaling and enables prion-like α-syn propagation [32], and ECM degradation products detected in the cerebrospinal fluid of patients with PD correlate with markers of synaptic dysfunction and clinical progression [33]. Together, this evidence challenges the view of the ECM as a passive scaffold and supports its active role in modulating synaptic vulnerability and PD pathogenesis [34]. Whereas previous systematic reviews have catalogued ECM-related transcriptional and proteomic alterations in PD [30,35], the present narrative review extends this body of work along three complementary axes that remain underdeveloped in the current literature. First, it integrates ECM dysregulation with synaptic-level mechanisms, specifically integrin β1–FAK/Src signaling, GluA1-AMPA receptor anchoring, and perineuronal net stability around parvalbumin-positive interneurons. Second, it critically appraises ECM-derived neoepitopes (C1M, C4M) as candidate prodromal and prognostic biomarkers, including their comparative performance against neurofilament light chain and their limitations regarding CNS specificity. Third, it provides a stratified evaluation of ECM-targeted therapeutic strategies in PD organized by level of clinical evidence, distinguishing experimental concepts from preclinical findings and from interventions with early human data. This integrative framing positions the ECM not merely as a dysregulated compartment but as a mechanistic node connecting synaptic vulnerability, biomarker development, and disease-modifying therapy. Establishing whether ECM dysregulation is a cause or a consequence of neurodegeneration is challenging in cross-sectional human studies. Nevertheless, several lines of evidence argue for an early pathogenic role: (i) iPSC-derived dopaminergic neurons carrying PD-linked mutations exhibit ECM transcriptome changes long before overt cell death [36,37]; (ii) in the A53T mouse, PNN fragmentation precedes significant dopaminergic loss [38,39]; and (iii) circulating ECM neoepitopes are elevated in prodromal cohorts, correlating with subsequent motor progression independently of baseline neuronal injury markers [40,41]. These observations suggest that ECM remodeling can initiate synaptic instability and glial activation, which in turn accelerate α-syn pathology and neurodegeneration, forming a feed-forward loop. Future longitudinal studies with inducible genetic models will be needed to definitively resolve causality.

2. Transcriptomic and Proteomic Foundations of Extracellular Matrix Dysregulation in PD

High-throughput transcriptomic profiling (RNA-seq) of SNpc tissue from PD cohorts, including specimens from the Harvard Brain Tissue Resource Center and the NINDS NeuroBioBank, has revealed widespread transcriptomic changes in PD, with many differentially expressed genes mapping to ECM pathways [26,40]. Structural basement membrane collagens (COL4A1, COL4A2, COL6A1/2) are consistently downregulated, while matrix metalloproteinases (MMP9, MMP13, MMP14) and their endogenous inhibitors TIMP1 and TIMP3 show altered expression, indicating a shift toward ECM degradation in dopaminergic regions [31,42]. Gene set enrichment analyses (GSEA) consistently identify " ECM structural constituent " and " ECM organization " among the most downregulated biological processes, supporting progressive disassembly of extracellular scaffolding in vulnerable nigrostriatal circuits [26,40,43,44]. Single-cell RNA sequencing (scRNA-seq) of dopaminergic neurons derived from iPSCs, including isogenic disease-control platforms [45], confirms these findings and shows reductions in transcripts linked to focal adhesion and synaptic anchoring, particularly ITGB1 and VCL [36,37]. At the protein level, integrin β1 clustering activates focal adhesion kinase (FAK) through autophosphorylation at Tyr397, which recruits Src family kinases and triggers a cascade that phosphorylates key postsynaptic scaffolds such as p130Cas and paxillin. This signaling stabilizes the actin cytoskeleton and promotes the synaptic retention of AMPA receptors by facilitating CaMKII-dependent phosphorylation of GluA1 at Ser831. Loss of ITGB1 therefore weakens this entire structural-signaling module, leading to dendritic simplification, reduced density of PSD95-positive excitatory synapses, and impaired excitatory transmission [46,47]. Proteomic studies using LC-MS/MS of cerebrospinal fluid (CSF) from patients with early-stage PD show persistent activation of ECM remodeling pathways [48], with elevated concentrations of collagenolytic neoepitopes (C1M and C4M) consistent with increased metalloproteinase activity in the CNS [49]. These ECM-derived fragments correlate with phosphorylated α-syn (Ser129) and indices of synaptic injury, suggesting their potential use as prodromal biomarkers of disease progression [50,51]. Together, these results reinforce the view that ECM breakdown is an early, mechanistically relevant event in PD pathogenesis that may precede overt synapse loss and neurodegeneration as summarized in Table 1 [17,52].
Table 1. Summary matrix of extracellular matrix components dysregulated in Parkinson’s disease: alterations, mechanistic consequences, evidence base, and translational implications.

3. Evidence from Animal Models and Human Studies

Experimental evidence from animal models and human neuropathological studies supports ECM dysregulation as a central contributor to the pathophysiology of PD, closely linked to synaptic dysfunction, neuroinflammatory responses, and progressive neurodegeneration [62,75]. In transgenic mouse models overexpressing mutant α-syn, particularly the A53T variant, early disruption of PNNs has been documented. Histological analyses using Wisteria floribunda agglutinin staining show fragmentation of PNNs in the striatum and cortex, with a 50–60% reduction in ECM-associated cell labeling by six months of age [38,39]. These structural changes coincide with progressive synaptic degeneration, reduced dopaminergic projections from the substantia nigra, and increased propagation of pathogenic α-syn aggregates [76,77]. Functional studies show that enzymatic ECM remodeling increases neuronal vulnerability: genetic ablation or pharmacological inhibition of matrix metalloproteinase-9 partially restores dopaminergic neuron integrity, increasing tyrosine hydroxylase–positive cell counts in the SNpc and reducing synaptic degeneration in α-syn transgenic models [64,65]. Together, these findings implicate metalloproteinase-mediated ECM breakdown as a mechanism of dopaminergic neurodegeneration [66]. Toxin-based models, particularly the MPTP mouse model, reproduce key features of sporadic PD. MPTP exposure induces ECM remodeling within the nigrostriatal axis, with accumulation of fragmented hyaluronic acid and other ECM degradation products in the striatal extracellular space [55,56]. Studies in both mouse and non-human primate MPTP models show that MMP-9 contributes to inflammatory glial activation and nigrostriatal degeneration [63]. These ECM fragments trigger innate immune signaling via pattern-recognition receptors, particularly Toll-like receptors, on astrocytes and microglia, promoting the neurotoxic A1 astrocyte phenotype with sustained pro-inflammatory mediator release and impaired synaptic maintenance [57,78,79]. These observations anticipate a self-reinforcing cycle linking ECM breakdown, glial activation, and α-syn accumulation that is developed mechanistically in Section 6.
Neuropathological analyses of human post-mortem tissue show extensive ECM remodeling in advanced PD, particularly within motor and cognitive circuits [26,40]. Aggrecan and other key PNN constituents are reduced in the hippocampus, prefrontal cortex, and other limbic and cortical regions [22,54]. Because aggrecan is a principal proteoglycan supporting synaptic stability and network integrity [17], its depletion contributes to synaptic destabilization and impaired plasticity in memory and learning domains. Clinically, these ECM alterations are associated with cognitive decline and reduced neuropsychological performance, particularly in PD dementia [12]. Multi-omics studies in human cohorts further support the link between ECM dysregulation and PD pathogenesis. Transcriptomic and genetic datasets from consortia such as the Parkinson Progression Marker Initiative (PPMI) [80] and the UK Biobank consistently show alterations in ECM organization, focal adhesion, and ECM receptor interaction pathways in both sporadic and familial PD [26,35]. Single-nucleus RNA sequencing also identifies microglial subpopulations with an “ECM-high” transcriptional signature, characterized by elevated metalloproteinases, integrins, and pro-inflammatory mediators, suggesting neuroimmune-ECM crosstalk in disease progression [40,81]. Overall, evidence from animal models and human neuropathology positions ECM instability as a central determinant of synaptic vulnerability, prion-like α-syn spread, and neuroinflammation in PD [40,64,78].

4. Emerging Biomarkers Originating from the Extracellular Matrix

Sensitive biomarkers that can track PD progression during prodromal stages, when synaptic dysfunction precedes overt neurodegeneration, remain an unmet need [26,40]. ECM-derived neoepitopes, generated by proteolytic cleavage of matrix constituents through matrix metalloproteinase activity, have emerged as candidate biomarkers of active remodeling and neurodegenerative processes [41,64]. Quantification of circulating collagen fragments such as C1M and C4M in serum using enzyme-linked immunosorbent assays enables detection of altered ECM turnover in neurological disorders [49,82]. In PD, these biomarkers track disease trajectory longitudinally, reflecting synaptic remodeling and basement membrane integrity [41]. Longitudinal cohort studies support the clinical utility of ECM-derived biomarkers: elevated baseline C1M and C4M levels in cohorts such as ICICLE-PD independently predict accelerated clinical deterioration, as assessed by the Unified Parkinson’s Disease Rating Scale [83,84]. Increased serum concentrations of these neoepitopes correlate with greater annual increases in UPDRS scores, supporting their value as early indicators of rapid disease progression [26,66]. Comparative analyses show that ECM fragments provide complementary or, in some studies, stronger prognostic information than established neurodegeneration biomarkers such as neurofilament light chain [79,82,85], with receiver operating characteristic analyses showing improved predictive performance for ECM-related measures [79,82]. Importantly, ECM remodeling biomarkers capture upstream pathophysiological processes that precede irreversible neuronal injury. The identification of patient subgroups with persistently elevated ECM biomarkers, termed “ECM-high progressors”, has advanced prognostic stratification by identifying individuals with aggressive disease trajectories and sustained extracellular remodeling activity [86,87]. Elevated circulating C1M is associated with advanced neuropathological stages and a greater burden of non-motor symptoms, including cognitive impairment and autonomic dysfunction [40,41]. These findings support ECM-based biomarkers as useful tools for risk stratification and for identifying patients with accelerated progression. From a translational perspective, ECM-derived biomarkers reflect active, upstream remodeling processes rather than end-stage neuronal damage [66]. ECM-based stratification strategies may therefore help optimize patient selection and enrichment in clinical trials targeting neuroinflammation, synaptic resilience, or ECM modulation [26,41].

5. Synaptic Remodeling and Pathological Dissemination of α-Syn

The ECM is a key regulator of synaptic plasticity and neuronal circuit stability, acting through integrin-β1 and focal adhesion complexes that include focal adhesion kinase (FAK) and Src family kinases [17,20]. Under physiological conditions, this signaling axis supports long-term potentiation via calcium-dependent kinases such as CaMKII and promotes phosphorylation of postsynaptic receptor subunits, maintaining excitatory synaptic transmission [88,89]. The structural and functional contrasts between the physiological and pathological ECM in the synaptic microenvironment of PD are summarized in Figure 1.
Figure 1. Structural and functional remodeling of the extracellular matrix in the synaptic microenvironment of Parkinson’s disease. Schematic comparison of the synaptic microenvironment under physiological and pathological conditions. (Left): Structural ECM components—collagen IV, laminin, and proteoglycans—together with integrin β1 (ITGB1)–focal adhesion kinase (FAK) signaling, sustain stable GluA1-AMPA receptor anchoring, controlled synaptic plasticity, and an intact blood–brain barrier (BBB). (Right): In PD, MMP–driven ECM degradation disrupts ITGB1–FAK signaling, destabilizes the postsynaptic density, and compromises BBB integrity. ECM remodeling promotes the prion-like propagation of misfolded α-synuclein (α-syn) through extracellular release and exosome-mediated transfer. ECM-derived signals engage Toll-like receptors 2 and 4 (TLR2/TLR4) on glial cells, triggering NF-κB activation, reactive astrogliosis, microglial activation, and pro-inflammatory cytokine release (IL-1β, TNF-α). Created in BioRender. Perez Rubio R. (2026) https://BioRender.com/m0c60pz (accesed on 26 May 2026).
Activation of these pathways recruits and stabilizes AMPA receptor subunits, particularly GluA1, within the postsynaptic density, supporting synaptic strength and plasticity [90,91]. In addition to local synaptic effects, integrin-FAK signaling engages downstream survival and plasticity pathways. FAK can activate the Ras-ERK cascade, promoting CREB phosphorylation and the transcription of synaptic plasticity-related genes such as BDNF [92]. Likewise, FAK-dependent PI3K-Akt signaling supports neuronal survival and the maintenance of synaptic spine density [93]. Dysregulation of these pathways in PD further compromises the capacity of neurons to sustain long-term potentiation and to counteract excitotoxic stress, thereby exacerbating synapse loss. In PD, disruption of integrin–FAK/Src signaling destabilizes postsynaptic architecture and reduces anchoring of GluA1-containing receptors, impairing excitatory neurotransmission and synaptic resilience [17,40]. Structural alterations of the ECM further promote the pathological spread of α-syn through mechanisms resembling prion-like propagation across interconnected neuronal networks [85]. ECM fragmentation and instability of perineuronal nets alter the extracellular space, modulating extracellular vesicle trafficking and intercellular communication [22,64]. These changes facilitate the release and uptake of pathogenic α-syn species via exosomes enriched in ECM remodeling proteins [94,95]. Altered ECM dynamics also promote the formation of tunneling nanotubes, enabling direct intercellular transfer of α-syn aggregates and their synapse-to-synapse spread along neuronal circuits [96,97]. Human astrocytes can also transfer aggregated α-syn to neighboring astrocytes via direct contact and tunneling nanotubes when their lysosomal degradation capacity is exceeded [98]. During neuroinflammatory states, matrix metalloproteinases degrade perineuronal net structures that surround parvalbumin-positive interneurons [22,66]. This enzymatic cleavage exposes inhibitory interneurons to oxidative stress and extracellular toxins, impairing local modulation of inhibitory tone within neural circuits [22,64]. Loss of this structural protection promotes excitotoxic conditions that destabilize synaptic networks and accelerate dopaminergic degeneration within the nigrostriatal pathway [40,81]. Reduction in basement membrane collagens, particularly type IV collagen, further weakens synaptic microenvironment stability by disrupting basement membrane integrity and altering adhesion complexes that support presynaptic vesicle docking and neurotransmitter release [42,64]. ECM instability may therefore facilitate altered vesicular trafficking and the pathological release of toxic α-syn species from presynaptic terminals into the extracellular space [40,85]. Overall, these mechanisms link synaptic dysfunction with proteopathic spread, making neuronal circuits progressively more vulnerable as PD advances [42,64].

6. Neuroinflammatory Responses Driven by ECM Remodeling

Pathological remodeling of the ECM strongly influences neuroinflammatory cascades in PD, linking synaptic injury, glial activation, and α-syn propagation [64,81]. Degradation of structural ECM components releases soluble fragments that act as damage-associated molecular patterns (DAMPs), initiating innate immune signaling within the CNS [99]. Among these ECM-derived DAMPs, biglycan and low-molecular-weight hyaluronic acid engage pattern recognition receptors such as Toll-like receptor 2 (TLR2) and Toll-like receptor 4 (TLR4) on microglia [58,59]. Engagement of these receptors activates intracellular signaling pathways, including the NF-κB and MAPK cascades, leading to upregulation of reactive oxygen species and pro-inflammatory cytokines such as IL-1β, TNF-α, and IL-6 [60,61]. This neuroinflammatory environment increases oxidative stress and impairs synaptic function within the nigrostriatal pathway. ECM-driven inflammatory signals can directly modulate α-syn pathology: exposure of dopaminergic neurons to inflammatory cytokines and oxidative stress promotes phosphorylation of α-syn at Ser129, a post-translational modification associated with pathological aggregation and Lewy body formation [100,101]. The extracellular release of α-syn aggregates activates microglia, amplifying inflammatory signaling and further ECM degradation [102,103]. Matrix remodeling, glial activation, and α-syn propagation thus reinforce one another in a positive feedback loop: ECM-derived DAMPs engage TLR2/TLR4 to drive glial activation; activated glia release MMPs that further degrade ECM and disrupt synaptic anchoring; and the resulting extracellular environment facilitates α-syn release, uptake, and aggregation, which in turn perpetuates microglial activation. This self-reinforcing cycle represents a unifying mechanistic framework for the convergence of ECM dysregulation, neuroinflammation, and proteopathic spread in PD.
Genetic determinants can intensify this neuroinflammatory ECM-glial axis by altering vesicular trafficking and immune signaling. For example, pathogenic LRRK2 variants, particularly the G2019S mutation, increase phosphorylation of Rab GTPases involved in vesicle transport, altering astrocyte and microglial secretion of inflammatory mediators and ECM components [104,105,106]. This produces elevated levels of inflammatory ECM fragments in the extracellular space, shifting microglial polarization toward neurotoxic phenotypes and worsening reactive astrogliosis [78]. Experimental models using patient-derived iPSC brain organoids support these mechanisms: pharmacological blockade of TLR signaling reduces glial activation and cytokine production, supporting an active contribution of ECM-derived inflammatory cues to neurodegenerative cascades [26,81]. Together, these findings implicate ECM remodeling as a central driver of neuroinflammation in PD, linking extracellular structural damage, innate immune activation, and progressive neuronal dysfunction [64,66].

7. Convergence with Traditional Pathways in Parkinson’s Disease

ECM disruption intersects with canonical pathogenic processes in PD, including mitochondrial dysfunction, impaired proteostasis, and chronic neuroinflammation [4,107]. Structural ECM elements influence the spatial organization of intracellular signaling networks, including pathways relevant to mitochondrial quality control through integrin-mediated mechanotransduction and cytoskeletal coupling [20]. A proposed mechanistic model linking collagen IV to PINK1/Parkin-mediated mitophagy posits that type IV collagen, through its binding to integrin α1β1 and dystroglycan complexes, couples the extracellular matrix to the actin cytoskeleton and, via cytoskeletal continuity, to the peri mitochondrial scaffold. Within this model, ECM–cytoskeletal coupling would help stabilize PINK1 accumulation on the outer membrane of depolarized mitochondria and facilitate Parkin recruitment and subsequent ubiquitination of outer-membrane substrates [53,108]. Loss of basement membrane collagens, particularly type IV collagen, would therefore be expected to disrupt this scaffold, impair mitophagic flux, and contribute to the accumulation of dysfunctional organelles in dopaminergic neurons. It should be emphasized, however, that this collagen IV integrin cytoskeleton PINK1/Parkin axis remains a working model: the individual molecular interactions are supported by evidence in non-neuronal systems, but the integrated cascade has not been formally demonstrated in dopaminergic neurons of PD models, and direct experimental validation in the parkinsonian context is still required.
ECM disruption also impairs neuronal proteostasis by altering cytoskeletal organization and intracellular trafficking pathways important for protein turnover and aggregate clearance [20]. Aggresome formation requires coordinated interactions between cytoskeletal elements and extracellular adhesion signals; when ECM integrity is lost, these processes are disrupted, promoting the accumulation of misfolded proteins such as α-syn [109,110]. Beyond the ECM+–neuroinflammation–α-syn cycle detailed in Section 6, inflammatory ECM fragments also amplify oxidative stress through TLR-mediated reactive oxygen species production, which in turn damages mitochondrial DNA, proteins, and lipids and compounds nigral neuron vulnerability [60,111,112]. These interconnected mechanisms position the ECM as a convergence point for multiple pathogenic pathways in PD [113]. Variability in extracellular microenvironment stability may explain the phenotypic heterogeneity observed among patients, influencing susceptibility to mitochondrial dysfunction, inflammatory signaling, and synaptic degeneration [11]. This framework may also help explain variable therapeutic responses, such as the suboptimal efficacy of L-DOPA, which could reflect chronic ECM instability that impairs synaptic plasticity and dopaminergic transmission [114,115]. The therapeutic implications of these convergent mechanisms are discussed in Section 8 tand are visually contextualized in Figure 2.
Figure 2. ECM-targeted therapeutic strategies in Parkinson’s disease. Schematic overview of four therapeutic approaches converging on the damaged synaptic microenvironment characteristic of Parkinson’s disease (PD). The central panel depicts a parkinsonian synapse with fragmented collagen IV fibers, degraded perineuronal net (PNN), extracellular α-synuclein aggregates, exosome-mediated propagation, activated microglia, and destabilized postsynaptic GluA1 (AMPA) and integrin β1 (ITGB1) receptors. (Top left): Doxycycline, a broad MMP inhibitor with preclinical evidence in PD models. (Top right): ATN-161, an integrin β1 antagonist peptide that disrupts focal adhesion kinase (FAK)/Src signaling, with phase 1 evidence in oncology. (Bottom left): Mesenchymal stem cells, which secrete tissue inhibitors of metalloproteinases (TIMPs) to restore the MMP–TIMP balance, supported by a randomized clinical trial in PD. (Bottom right): Chondroitinase ABC, an experimental approach modulating PNNs around parvalbumin-positive (PV+) interneurons. The level of clinical evidence in PD for each strategy is indicated by the color-coded tags. Created in BioRender. Perez Rubio, R. (2026) https://BioRender.com/d3j8z3s (accessed on 26 May 2026).

8. Therapeutic Implications: MMP Inhibitors and ECM Stabilization Approaches

Targeting the ECM represents a promising therapeutic approach for slowing the progression of PD [17,66]. Dysregulated MMP activity contributes to ECM degradation, and excessive MMP activation has been linked to neuronal injury and synaptic destabilization across neurodegenerative disorders [116]. Pharmacological inhibition of MMPs using repurposed agents such as doxycycline has shown neuroprotective effects in preclinical PD models [67,117]. In MPTP rodent models, doxycycline reduces microglial activation, limits ECM breakdown, and preserves dopaminergic neuron viability in the substantia nigra, with improvement in motor performance in behavioral assays [67]. These findings suggest partial restoration of synaptic architecture and neuronal survival; however, no randomized clinical trial of doxycycline has been completed in PD to date, and its broad-spectrum MMP inhibition together with the microbiome implications of chronic antibiotic exposure constrain straightforward translation. Disruption of ECM–integrin signaling pathways represents another potential therapeutic avenue [20]. Peptide-based inhibitors targeting integrin receptors, such as ATN-161, reduce inflammatory cell migration and microglial activation by blocking ECM–receptor interactions in cellular models [73,74]. ATN-161 has completed a phase 1 trial in patients with solid tumors, where it was well tolerated [73]; its application to PD, however, remains a conceptual extrapolation, with no PD-specific preclinical efficacy data or clinical trials currently available, and CNS penetration in a parkinsonian context has not been characterized. Modulation of PNNs using chondroitinase ABC, a strategy studied in spinal cord injury and stroke models, has been proposed as a conceptual approach to restore synaptic plasticity in PD. Direct evidence in PD models is currently lacking, and the underlying therapeutic question of whether PNNs in PD should be enzymatically digested to restore plasticity or, conversely, stabilized to preserve inhibitory interneuron function, remains conceptually unresolved [22,54]. At present, chondroitinase ABC in PD should be regarded as an experimental concept rather than a translational candidate. Cell-based strategies aimed at stabilizing the extracellular microenvironment are also under investigation. Bone marrow–derived mesenchymal stem cells secrete tissue inhibitors of metalloproteinases and immunomodulatory factors, potentially restoring the MMP–TIMP equilibrium in damaged neural tissue [70,71]. A recent single-center randomized trial of allogeneic bone marrow–derived MSCs in PD reported early safety and tolerability signals together with preliminary efficacy indicators, although the ECM-mediated mechanism of action in humans has not been formally demonstrated, long-term follow-up data remain pending, and multicenter replication is required before broader conclusions can be drawn [72]. The mechanisms of action, supporting evidence, clinical development stage, and key limitations of each of these strategies are detailed in Table 2. Taken together, ECM-targeted strategies in PD currently span four distinct levels of translational maturity: (i) experimental concepts without direct PD data (chondroitinase ABC, selective MMP-3 inhibition); (ii) preclinical evidence in PD-relevant models (doxycycline, MMP-9 inhibition); (iii) clinical-stage agents tested outside PD and proposed for repurposing (ATN-161); and (iv) interventions with early human data in PD (allogeneic mesenchymal stem cells, single randomized trial). No ECM-targeted intervention has yet established disease-modifying efficacy in PD through a confirmatory phase 3 trial. Recognition of these tiers is essential to avoid conflating mechanistic plausibility with clinical readiness.
Table 2. Extracellular matrix-targeted therapeutic strategies in Parkinson’s disease: mechanism, evidence, and limitations.

9. Biomarkers and Patient Classification

Biomarkers arising from ECM remodeling represent a useful resource for molecular stratification of PD patients, enabling classification based on underlying pathological mechanisms [118,119]. Proteolytic degradation of structural matrix proteins generates circulating neoepitopes detectable in blood and cerebrospinal fluid, such as C1M and C4M, which show promise as indicators of disease activity and ECM remodeling [120,121]. Elevated levels of these neoepitopes correlate with more aggressive clinical trajectories, including accelerated motor decline and worsening non-motor symptoms [122,123]. The identification of ECM-high progressors—a patient subgroup with persistently elevated ECM biomarker levels and rapid disease progression—offers a basis for patient stratification in clinical trials of ECM-targeted or anti-inflammatory therapies [124]. ECM-derived biomarkers measured in peripheral blood offer practical advantages over more invasive approaches such as lumbar puncture [125]. These biomarkers also capture upstream pathological alterations that precede irreversible neuronal injury, making them useful for early detection and longitudinal monitoring of therapeutic efficacy. Together, ECM-linked biomarkers have potential for advancing personalized medicine and precision care in PD [126].

10. Discussion

The multi-omics evidence synthesized in this review supports a central role of the ECM in the synaptic pathophysiology of PD, beyond its traditional function as a passive structural scaffold [17,22,26]. Analyses combining transcriptomic, proteomic, spatial proteomic, and single-cell sequencing datasets show consistent alterations in key ECM components including basement membrane collagens, proteoglycans, and perineuronal network constituents alongside dysregulation of MMPs, TIMPs, and integrin signaling pathways [31,66,85]. These molecular changes affect synaptic stability, dopaminergic neuron vulnerability, and the propagation of α-syn aggregates throughout neural circuits [13,26,108]. This framework connects idiopathic and genetic forms of PD, integrating prior mechanistic models centered on mitochondrial dysfunction, protein aggregation, or neuroinflammation [26,110]. The focus on ECM biology also offers practical translational advantages: ECM-derived biomarkers are accessible in serum or cerebrospinal fluid, supporting early patient stratification and disease monitoring [11]. Consistent validation across experimental platforms including human cohorts, animal models, and cellular systems supports these findings [26,81]. Gene set enrichment analyses across datasets identify dysregulation of pathways governing ECM organization, focal adhesion, and synaptic remodeling, supporting the biological plausibility of ECM dysfunction as a central link between synaptic pathology, neuroinflammation, and clinical progression [20,31]. The ECM offers practical advantages over conventional intracellular targets. Whereas intracellular pathways are often resistant to pharmacological modulation, the ECM is comparatively accessible and pharmacologically tractable [116]. Peripheral stratification using circulating ECM-derived biomarkers, such as collagen neoepitopes, could guide precision targeting of disease-modifying interventions toward those most likely to benefit [118]. Within this framework, inhibition of pathological ECM remodeling represents a testable model for slowing PD progression by preserving synaptic architecture and neuronal microenvironmental stability [17]. Future PD therapeutics will likely involve combinatorial approaches that integrate strategies targeting α-syn aggregation, mitochondrial dysfunction, and neuroinflammatory signaling with ECM stabilization [85,111].

Limitations

Most of the supporting evidence is correlational; definitive causal studies manipulating specific ECM components in human-relevant models remain scarce [11,26]. Publication bias toward positive ECM findings likely skews the available literature, with few negative or non-confirmatory reports [22]. The neuropathological heterogeneity of PD subtypes introduces confounding variability that has not been systematically controlled across cross-sectional cohorts and complicates the interpretation of group-level ECM signatures [15]. Reports of MMP expression in post-mortem nigral tissue show variable directionality across MMP family members and disease stages [65], and single-cell transcriptomic signatures attributed to ECM-high microglial subpopulations have not been consistently replicated across all published datasets [40,81]. Whether perineuronal net fragmentation precedes or follows dopaminergic loss in early disease also remains mechanistically unresolved [22,38]. Limitations specific to ECM-derived biomarkers: The translational case for C1M and C4M as prognostic biomarkers in PD rests on a small number of cohorts, notably ICICLE-PD, and lacks prospective multicenter validation [41,84]. These neoepitopes are not central nervous system–specific: collagen turnover from peripheral tissues, including liver, kidney, and vasculature, contributes to circulating levels, raising concerns about specificity in older patients with frequent systemic comorbidities [49,121]. Reference ranges, assay standardization, and clinically actionable cut-points are not yet established. Comparative performance against neurofilament light chain rests on limited head-to-head data, and definitive superiority of ECM-derived neoepitopes over NfL cannot be claimed at present [79,82]. No ECM-based biomarker has been validated for differential diagnosis between PD and atypical parkinsonian syndromes. Limitations of ECM-targeted therapeutic strategies. As detailed in Table 2, no ECM-targeted intervention has completed a confirmatory randomized clinical trial in PD, except for a single-center preliminary mesenchymal stem cell study [72]. Central nervous system penetration, molecular target selectivity, and pharmacodynamic response biomarkers remain unresolved for most candidate agents. Whether ECM modulation should favor stabilization or controlled degradation of specific structures, such as perineuronal nets, also remains conceptually unresolved.

11. Concluding Remarks and Future Directions

The evidence synthesized in this review supports ECM dysregulation as an active contributor to PD pathogenesis, linking synaptic dysfunction, neuroinflammation, and prion-like α-syn propagation [17,85]. Remodeling of structural ECM constituents—including basement membrane collagens, proteoglycans, and PNNs— shapes the neuronal microenvironment that supports synaptic integrity and dopaminergic resilience and influences the susceptibility of neural circuits to mitochondrial dysfunction, glial activation, and proteopathic spread [19,20,85,107]. The relative accessibility of the ECM, compared with intracellular targets, and the availability of peripheral ECM-derived biomarkers, such as collagen neoepitopes detectable in blood, offer a practical path from mechanistic insight to clinical application, with utility in early patient stratification, longitudinal disease monitoring, and biomarker-guided trial design [49,118,119,125]. Therapeutic strategies targeting matrix MMP activity, integrin signaling, and ECM turnover represent reasonable candidates for preserving synaptic architecture and neuronal viability; clinical translation will require in vivo validation and international collaboration [17,26,116,118]. Future investigations should employ experimental systems that recapitulate the structural and molecular complexity of the human brain [26,127]. iPSC-derived midbrain organoids integrated with three-dimensional bioprinted scaffolds incorporating collagen IV, aggrecan, and perlecan may allow more faithful reconstruction of disease-relevant microenvironments [22,54]. Combining these platforms with high-throughput multi-omics, spatial proteomics, and single-cell chromatin accessibility profiling can provide longitudinal data on ECM remodeling across PD progression [26,111]. Large-scale, standardized datasets analyzed with artificial intelligence and machine learning may help identify optimal therapeutic windows and biomarker signatures [118]. Genome-editing technologies such as CRISPR–Cas9 may enable targeted modulation of ECM-related genes, potentially preserving perineuronal nets and synaptic architecture in vivo [17,104,116]. Achieving these goals will require global consortia, standardized biobanking, and coordinated research initiatives [26,118]. By integrating bioengineering, multi-omics, computational analytics, and precision medicine, PD may be reframed as a stratifiable and modifiable disorder in which ECM represents a biologically relevant and therapeutically tractable axis [85,118].

Author Contributions

Conceptualization, investigation, writing and original draft: C.R., R.P.-R. and M.R.-O.; writing—review, editing and data curation: J.P.-V., N.S.-G., Á.L., L.G.-R. and M.T.-S. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Data Availability Statement

Not applicable. This article is a narrative review and did not generate new data.

Acknowledgments

The authors have reviewed and edited the output and take full responsibility for the content of this publication.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
α-synAlpha-synuclein
ACANAggrecan
AMPAα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
ATN-161Ac-PHSCN-NH2 (integrin β1 antagonist peptide)
BBBBlood–brain barrier
CaMKIICa2+/calmodulin-dependent protein kinase II
CNSCentral nervous system
COL4A1/A2Collagen type IV, alpha 1/alpha 2
COL6A1/A2Collagen type VI, alpha 1/alpha 2
CRISPR–Cas9Clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9
CSFCerebrospinal fluid
CSPGChondroitin sulfate proteoglycan
C1MMMP-generated type I collagen neoepitope
C4MMMP-generated type IV collagen neoepitope
DADopaminergic
DAMPDamage-associated molecular pattern
ECMExtracellular matrix
ELISAEnzyme-linked immunosorbent assay
FAKFocal adhesion kinase
GBAGlucocerebrosidase
GluA1Glutamate receptor AMPA subunit 1
GSEAGene set enrichment analysis
GTPaseGuanosine triphosphatase
HAHyaluronan
ICICLE-PDIncidence of Cognitive Impairment in Cohorts with Longitudinal Evaluation in Parkinson’s Disease
IL-1βInterleukin 1 beta
IL-6Interleukin 6
iPSCInduced pluripotent stem cell
ITGB1Integrin beta 1
KOKnockout
L-DOPALevodopa
LC-MS/MSLiquid chromatography–tandem mass spectrometry
LRRK2Leucine-rich repeat kinase 2
LTPLong-term potentiation
MAPKMitogen-activated protein kinase
MMPMatrix metalloproteinase
MPTP1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
MSCMesenchymal stem cell
MWMolecular weight
NF-κBNuclear factor kappa B
NfLNeurofilament light chain
NINDSNational Institute of Neurological Disorders and Stroke
PDParkinson’s disease
PFCPrefrontal cortex
PINK1PTEN-induced kinase 1
PNNPerineuronal net
PPMIParkinson Progression Marker Initiative
PRKNParkin RBR E3 ubiquitin protein ligase
PSD95Postsynaptic density protein 95
PV+Parvalbumin-positive
RabRas-related protein
RNA-seqRNA sequencing
ROSReactive oxygen species
scRNA-seqSingle-cell RNA sequencing
Ser129Serine 129
SNpcSubstantia nigra pars compacta
SNCASynuclein alpha gene
SrcProto-oncogene tyrosine-protein kinase Src
THTyrosine hydroxylase
TIMPTissue inhibitor of metalloproteinase
TLR2Toll-like receptor 2
TLR4Toll-like receptor 4
TNF-αTumor necrosis factor alpha
UPDRSUnified Parkinson’s Disease Rating Scale
VCLVinculin
VDACVoltage-dependent anion channel

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