Biology subjects

Gunnersen, J. M.

Publications and source records attributed to Gunnersen, J. M..

4 recordsLinked to original sources

bioRxiv2026

SEZ6L2 Loss Disrupts Motor Coordination, Cognitive Function, and Synaptic Connectivity

The SEZ6 family, composed of SEZ6, SEZ6L, and SEZ6L2, plays essential roles in neurodevelopment, synaptic organization, and complement regulation. However, the specific contribution of SEZ6L2 to brain function remains largely unexplored. In this study, we provide the first comprehensive behavioral and neurobiological characterization of Sez6l2 knockout (KO) mice and directly compare their phenotype with Sez6 triple knockout (TKO) mice, which lack all three Sez6 family genes. Sez6l2 KO mice exhibit impairments across multiple behavioral domains, including motor coordination, gait, sociability, sensory processing, and goal-directed repetitive behaviors. Several phenotypes, particularly motor deficits, worsen with age. Male Sez6l2 KO mice also demonstrate enhanced fear learning and increased prepulse inhibition, revealing sex-specific alterations in sensorimotor gating. At the synaptic level, Sez6l2 KO mice show reduced dendritic spine length and decreased expression of key postsynaptic proteins suggesting impaired excitatory synaptic connectivity. These structural and molecular abnormalities likely contribute to the observed behavioral deficits. In comparison, Sez6 TKO mice display more severe impairments across most measures. Together, these findings establish SEZ6L2 as a critical and non-redundant regulator of motor, cognitive, and synaptic function and provide mechanistic insight into how dysfunction within the SEZ6 family may contribute to neurodevelopmental and neurodegenerative disorders.

neuroscience↗

bioRxiv2021

Inhibition of striatal SEZ6 by miR-3594-5p is a drug-specific marker for late-stage heroin intake escalation

Escalation of drug use is a hallmark stage in the transition to addiction and uncovering its underlying brain molecular mechanisms constitutes a considerable challenge. Here, we report in rats with extended access to heroin for self-administration that miR-3594-5p was upregulated in the dorsal striatum at late, but not early, stages during escalation when excessive heroin intake plateaued. Striatal miR-3594-5p bound directly to the 3UTR region of Sez6 transcript and inhibited its expression, thereby decreasing the mature form of the translated SEZ6 protein. This miR-3594-5p/Sez6 interaction was specific to heroin, as it was not observed with cocaine, and correlated with the severity of heroin intake escalation. Our findings reveal that miRNA alterations during escalation of drug self-administration are spatially and temporally regulated and drug-specific.

neuroscience↗

bioRxiv2020

The Sez6 family inhibits complement at the level of the C3 convertase.

The Sez6 family consists of Sez6, Sez6L, and Sez6L2. Its members are expressed throughout the brain and have been shown to influence synapse numbers and dendritic morphology. They are also linked to various neurological and psychiatric disorders. All Sez6 family members contain 2-3 CUB domains and 5 complement control protein (CCP) domains, suggesting that they may be involved in complement regulation. We show that all Sez6 family members inhibit C3 deposition by the classical and alterative pathways with varying degrees of efficacy. For the classical pathway, Sez6 is a strong inhibitor, Sez6L2 is a moderate inhibitor, and Sez6L is a weak inhibitor. Using Sez6L2 as the representative family member, we show that it specifically deactivates C3 convertases by accelerating the decay or dissociation of the C3 convertase components. Sez6L2 also deactivates C3 convertases of the alternative pathway by serving as a cofactor for Factor I to facilitate the cleavage of C3b. However, Sez6L2 has no cofactor activity toward C4b. In summary, the Sez6 family are novel complement regulators that inhibit C3 convertases.

neuroscience↗

bioRxiv2017

Legionella protection and vaccination mediated by Mucosal Associated Invariant T (MAIT) cells

Mucosal associated invariant T (MAIT) cells recognize conserved microbial metabolites from riboflavin synthesis. Striking evolutionary conservation and pulmonary abundance implicate them in antibacterial host defense, yet their roles in protection against clinically significant pathogens are unknown. Murine Legionella infection induced MR1-dependent MAIT cell activation and rapid pulmonary accumulation of MAIT cells associated with immune protection detectable in fully immunocompetent host animals. MAIT cell protection was more evident in mice lacking CD4+ cells, whilst profoundly immunodeficient RAG2-/-{gamma}C-/- mice were substantially rescued from uniformly lethal Legionella infection by adoptively-transferred MAIT cells. This protection was dependent on MR1, IFN-{gamma} and GM-CSF, but not IL-17, TNF- or perforin. Protection was enhanced and observed earlier post-infection in mice that were Ag-primed to boost MAIT cells before infection. Our findings define a significant role for MAIT cells in protection against a major human pathogen and indicate a potential role for vaccination to enhance MAIT cell immunity.

immunology↗