Biology subjects

Duvernay, J.

Publications and source records attributed to Duvernay, J..

3 recordsLinked to original sources

bioRxiv2026

Preformed Fibril Seeding Reshapes the Phosphorylated α-Synuclein Proximal Proteome in the Olfactory Bulb

BackgroundAggregated alpha-synuclein (syn) phosphorylated at serine 129 (PS129) accumulates in synucleinopathies, with the olfactory bulb (OB) being severely affected. Non-aggregated physiological PS129 is abundant in the mammalian OB, where it likely modulates syn-protein interactions. The impact of aggregation on the PS129 interactome in the OB remains unclear. We hypothesized that syn aggregation alters the PS129 interactome, shifting canonical synaptic partners (e.g., SNARE proteins) toward the aggregate-associated network. To test this hypothesis, we mapped PS129 interactions in the OB of PFF-injected WT and SNCAA53T/A53T (M83) mice using biotinylation by antibody recognition (BAR) and pretreated with calf-intestine alkaline phosphatase (CIAP) to distinguish physiological from aggregate-associated PS129 interactomes. Seeding and spread were assessed by immunohistochemistry and in situ seeding immunodetection assay (isSID). ResultsFollowing OB-PFF injections, CIAP-resistant aggregates and seeds were detected throughout the neuroaxis of M83 mice (e.g., OB to brainstem) but less so in WT mice. isSID seeding was concentrated near CIAP-resistant aggregates, but the overlap was only partial. BAR-PS129 identified 2,309 proteins in M83 OBs and 990 proteins in WT OBs. Of these, 357 proteins in M83 mice and 247 proteins in WT mice were associated with the CIAP-resistant, aggregate-enriched PS129 fraction. In both models, the CIAP-resistant interactome largely overlapped with the broader PS129 interactome, suggesting that seeded aggregation primarily affects existing PS129 interactions rather than directing the formation of new pathological ones. A conserved 107-protein CIAP-resistant signature shared between M83, and WT mice was enriched for axon-glia adhesion, myelin-associated, axonal/cytoskeletal, proteostatic, and synaptic vesicle-related proteins. ConclusionAggregated PS129 engages a subset of PS129 networks enriched at axon-glial interfaces. CIAP-resistant aggregates were partially associated with seed competency, indicating that CIAP resistance and seed competency are related but not equivalent. These results provide molecular details of syn seeding and spread from the OB.

neuroscience↗

bioRxiv2025

CD11b Activation Reduces Myeloid Brain Infiltration and Mitigates Synucleinopathy in a Model of Parkinson's Disease

The pathology of Parkinsons disease is defined by -synuclein (-syn) aggregation into neuronal Lewy bodies, which may lead to chronic neuroinflammation and dopaminergic neurodegeneration. Misfolded -syn activates Toll-like receptor signaling in microglia, leading to downstream activation of NF-{kappa}B and subsequent release of pro-inflammatory cytokines. These cytokines recruit pro-inflammatory myeloid cells from circulation, thereby amplifying neuroinflammation. Thus, reducing microglial activation and myeloid cell infiltration has the potential to reduce neuroinflammation and PD pathology. Here, we investigated a targeted immunomodulatory strategy using LA1, a novel, small-molecule agonist of CD11b, a {beta}2 integrin receptor highly and selectively expressed on myeloid cells and microglia. CD11b has key roles in cell adhesion, migration, and phagocytosis. Previous work has demonstrated that CD11b agonism via LA1 transiently enhances integrin-mediated adhesion that limits immune cell transmigration and tissue infiltration. CD11b agonism also suppresses TLR-driven inflammatory signaling and myeloid cell activation. To evaluate its efficacy in vivo, we utilized pre-clinical Parkinsons disease model by stereotaxically delivering AAV2-SYN to induce -synuclein overexpression in the murine midbrain. Mice were treated with oral LA1 for four or eight weeks and analyzed. LA1 treatment significantly reduced microglial activation and decreased brain infiltration of peripheral immune cells, thereby attenuating -synuclein-induced neuroinflammation. These findings suggest that CD11b agonism may offer a dual-action therapeutic approach in Parkinsons disease by dampening pro-inflammatory responses by central and peripheral myeloid cells.

neuroscience↗

bioRxiv2025

Alpha-synuclein phosphorylation is abundant in the non-synucleinopathy human brain

Phosphorylation of alpha-synuclein (syn) at serine 129 (PS129) marks aggregates in synucleinopathies but also occurs physiologically, potentially signaling protein interactions during neuronal activity. Technical barriers, including postmortem dephosphorylation, have hindered the study of physiological PS129 in the human brain. Using biotinylation by antibody recognition (BAR) on surgically resected temporal lobectomy tissues (without post-mortem interval), we mapped physiological PS129 and total syn interactomes. BAR identified 1,095 interactions with 513 syn-specific, 524 shared, and 58 PS129-specific, mostly associated with vesicles at presynaptic nerve terminals. PS129-specific interactions were uniquely associated with postsynaptic density proteins SHANK1/3, DLGAP1-4, DLGAP1-3, and DLG2-4, as well as nuclear-associated proteins HUWE1, HNRNPM, RBM14, ITCH, OGT, PHF24, and PPP2R5E. Fluorescent staining confirmed physiological PS129 proximal to dendrites and within the nucleus. Confirmation in healthy cynomolgus macaques (62% syn and 41% PS129 overlap) demonstrated that the interactomes were physiological rather than disease- or aggregate-associated. We conclude that physiological PS129 plays a unique and underappreciated role in postsynaptic neurons extending from the postsynaptic active zone to the nucleus. These interactomes benchmark normal syn biology, illuminating the transition to synucleinopathy pathology. Significance StatementDisease-associated syn phosphorylation (PS129) was recently identified in healthy mammalian brain and may signal syn-protein interactions during neuronal activity. Here, we surmounted technical hurdles and characterized syn and PS129 interactomes directly in the human brain. Results showed a unique significance for PS129 in post-synaptic active zones and nuclear compartments, which was confirmed in healthy non-human primates. These syn interactomes will be a valuable reference for understanding synucleinopathy mechanisms in the context of normal syn biology.

neuroscience↗