SARM1 acts downstream of neuroinflammatory and necroptotic signaling to induce axon degeneration

Neuroinflammation and necroptosis are major contributors to neurodegenerative disease, and axon dysfunction and degeneration is often an initiating event. SARM1 is the central executioner of pathological axon degeneration. Here, we demonstrate functional and mechanistic links among these three pro-degenerative processes. In a neuroinflammatory model of glaucoma, TNF-α induces SARM1-dependent axon degeneration, oligodendrocyte loss, and subsequent retinal ganglion cell death. TNF-α also triggers SARM1-dependent axon degeneration in sensory neurons via a noncanonical necroptotic signaling mechanism. MLKL is the final executioner of canonical necroptosis; however, in axonal necroptosis, MLKL does not directly trigger degeneration. Instead, MLKL induces loss of the axon survival factors NMNAT2 and STMN2 to activate SARM1 NADase activity, which leads to calcium influx and axon degeneration. Hence, these findings define a specialized form of axonal necroptosis. The demonstration that neuroinflammatory signals and necroptosis can act locally in the axon to stimulate SARM1-dependent axon degeneration identifies a therapeutically targetable mechanism by which neuroinflammation can stimulate axon loss in neurodegenerative disease

Putative cell adhesion membrane protein Vstm5 regulates neuronal morphology and migration in the central nervous system

During brain development, dynamic changes in neuronal membranes perform critical roles in neuronal morphogenesis and migration to create functional neural circuits. Among the proteins that induce membrane dynamics, cell adhesion molecules are important in neuronal membrane plasticity. Here, we report that V-set and transmembrane domain-containing protein 5 (Vstm5), a cell-adhesion-like molecule belonging to the Ig superfamily, was found in mouse brain. Knock-down of Vstm5 in cultured hippocampal neurons markedly reduced the complexity of dendritic structures, as well as the number of dendritic filopodia. Vstm5 also regulates neuronal morphology by promoting dendritic protrusions that later develop into dendritic spines. Using electroporationin utero, we found that Vstm5 overexpression delayed neuronal migration and induced multiple branches in leading processes during corticogenesis. These results indicate that Vstm5 is a new cell-adhesion-like molecule and is critically involved in synaptogenesis and corticogenesis by promoting neuronal membrane dynamics.SIGNIFICANCE STATEMENTNeuronal migration and morphogenesis play critical roles in brain development and function. In this study, we demonstrate for the first time that V-set and transmembrane domain-containing protein 5 (Vstm5), a putative cell adhesion membrane protein, modulates both the position and complexity of central neurons by altering their membrane morphology and dynamics. Vstm5 is also one of the target genes responsible for variations in patient responses to treatments for major depressive disorder. Our results provide the first evidence that Vstm5 is a novel factor involved in the modulation of the neuronal membrane and a critical element in normal neural circuit formation during mammalian brain development.</jats:p

Live imaging reveals the cellular events downstream of SARM1 activation

SARM1 is an inducible NA

Cellular and Tissue Selectivity of AAV Serotypes for Gene Delivery to Chondrocytes and Cartilage

Background: Despite several studies on the effect of adeno-associated virus (AAV)-based therapeutics on osteoarthritis (OA), information on the transduction efficiency and applicable profiles of different AAV serotypes to chondrocytes in hard cartilage tissue is still limited. Moreover, the recent discovery of additional AAV serotypes makes it necessary to screen for more suitable AAV serotypes for specific tissues. Here, we compared the transduction efficiencies of 14 conventional AAV serotypes in human chondrocytes, mouse OA models, and human cartilage explants obtained from OA patients. Methods: To compare the transduction efficiency of individual AAV serotypes, green fluorescent protein (GFP) expression was detected by fluorescence microscopy or western blotting. Likewise, to compare the transduction efficiencies of individual AAV serotypes in cartilage tissues, GFP expression was determined using fluorescence microscopy or immunohistochemistry, and GFP-positive cells were counted. Results: Only AAV2, 5, 6, and 6.2 exhibited substantial transduction efficiencies in both normal and OA chondrocytes. All AAV serotypes except AAV6 and rh43 could effectively transduce human bone marrow mesenchymal stem cells. In human and mouse OA cartilage tissues, AAV2, AAV5, AAV6.2, AAV8, and AAV rh39 showed excellent tissue specificity based on transduction efficiency. These results indicate the differences in transduction efficiencies of AAV serotypes between cellular and tissue models. Conclusions: Our findings indicate that AAV2 and AAV6.2 may be the best choices for AAV-mediated gene delivery into intra-articular cartilage tissue. These AAV vectors hold the potential to be of use in clinical applications to prevent OA progression if appropriate therapeutic genes are inserted into the vector

Mutation spectrum and biochemical features in infants with neonatal Dubin-Johnson syndrome

Abstract Background Dubin-Johnson syndrome (DJS) is an autosomal recessive disorder presenting as isolated direct hyperbilirubinemia.DJS is rarely diagnosed in the neonatal period. The purpose of this study was to clarify the clinical features of neonatal DJS and to analyze the genetic mutation of adenosine triphosphate-binding cassette subfamily C member 2 (ABCC2). Methods From 2013 to 2018, 135 infants with neonatal cholestasis at Seoul National University Hospital were enrolled. Genetic analysis was performed by neonatal cholestasis gene panel. To clarify the characteristics of neonatal DJS, the clinical and laboratory results of 6 DJS infants and 129 infants with neonatal cholestasis from other causes were compared. Results A total of 8 different ABCC2 variants were identified among the 12 alleles of DJS. The most common variant was p.Arg768Trp (33.4%), followed by p.Arg100Ter (16.8%). Three novel variants were identified (p.Gly693Glu, p.Thr394Arg, and p.Asn718Ser). Aspartate transaminase (AST) and alanine transaminase (ALT) levels were significantly lower in infants with DJS than in infants with neonatal cholestasis from other causes. Direct bilirubin and total bilirubin were significantly higher in the infants with DJS. Conclusions We found three novel variants in 6 Korean infants with DJS. When AST and ALT levels are normal in infants with neonatal cholestasis, genetic analysis of ABCC2 permits an accurate diagnosis

Unilateral Trigeminal Mandibular Motor Neuropathy Caused by Tumor in the Foramen Ovale

Pure trigeminal motor neuropathy is characterized by trigeminal motor weakness without signs of trigeminal sensory or other cranial nerve involvement. We describe a 63-year-old woman with progressive weakness and atrophy of the left masticatory muscles. She had no sensory disturbance. The diagnosis of pure trigeminal motor neuropathy was made on the basis of clinical and electrophysiologic studies. Magnetic resonance imaging of the brain revealed enhancement of the enlarged mandibular branch of the trigeminal nerve coursing through the left foramen ovale. Our observations suggest that pure trigeminal motor neuropathy can be induced by a tumor

Neurotoxins subvert the allosteric activation mechanism of SARM1 to induce neuronal loss

SARM1 is an inducible TIR-domain NA