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Schizophrenia risk is associated with increased gene copy number and brain expression of complement component 4 (C4). Because the complement system facilitates synaptic pruning, the C4 association has renewed interest in a hypothesis that excessive pruning contributes to schizophrenia pathogenesis. However, little is known about complement regulation in neural tissues or whether such regulation could be relevant to psychiatric illness. Intriguingly, common variation within CSMD1, which encodes a putative complement inhibitor, has consistently associated with schizophrenia at genome-wide significance. We found that Csmd1 is predominantly expressed in the brain by neurons, and is enriched at synapses; that human stem cell-derived neurons lacking CSMD1 are more vulnerable to complement deposition; and that mice lacking Csmd1 have increased brain complement activity, fewer synapses, aberrant complement-dependent development of a neural circuit, and synaptic elements that are preferentially engulfed by cultured microglia. These data suggest that CSMD1 opposes the complement cascade in neural tissues.Graphic Abstract.Our findings support a model in which CSMD1 opposes actions of the complement cascade in neural tissues (top left). We investigated two models in which Csmd1 was genetically ablated: human cortical neurons derived from embryonic stem cells, and a back-crossed C57bl6-Tac mouse line (top right). Csmd1 is normally expressed by neurons and present at synapses where it can protect them from complement (bottom left); in the absence of Csmd1 (bottom right), we find more deposition of complement (on cultured human cortical neurons and in the mouse visual system), reduced numbers of synapses (in the mouse visual system), and synaptic fractions that are more readily engulfed by microglia (ex vivo). Created with BioRender.com.

Neuronal circuit assembly requires the fine balance between synapse formation and elimination. Microglia, through the elimination of supernumerary synapses, have an established role in this process. While the microglial receptor TREM2 and the soluble complement proteins C1q and C3 are recognized as key players, the neuronal molecular components that specify synapses to be eliminated are still undefined. Here, we show that exposed phosphatidylserine (PS) represents a neuronal “eat‐me” signal involved in microglial‐mediated pruning. In hippocampal neuron and microglia co‐cultures, synapse elimination can be partially prevented by blocking accessibility of exposed PS using Annexin V or through microglial loss of TREM2. In vivo, PS exposure at both hippocampal and retinogeniculate synapses and engulfment of PS‐labeled material by microglia occurs during established developmental periods of microglial‐mediated synapse elimination. Mice deficient in C1q, which fail to properly refine retinogeniculate connections, have elevated presynaptic PS exposure and reduced PS engulfment by microglia. These data provide mechanistic insight into microglial‐mediated synapse pruning and identify a novel role of developmentally regulated neuronal PS exposure that is common among developing brain structures., Exposed phosphatidylserine on pre‐ and postsynaptic membranes functions as an “eat‐me” signal contributing to microglia‐mediated synapse pruning.

This review addresses two puzzling findings related to mutations in galactocerebrosidase (GALC) that cause Krabbe disease (KD), a severe lysosomal storage disorder characterized by extensive myelin damage in children with mutations in both GALC alleles. First, heterozygous carriers of KD-causing mutations, which include the biological parents of children with KD, exhibit increased risk for developing other diseases. Second, variants in the GALC locus increase the risk of developing multiple sclerosis (MS), another disease characterized by extensive myelin damage. What explains these correlations? In studies on cuprizone-induced myelin damage in heterozygous (GALC+/-) mice carrying one copy of a mutation that causes KD-like disease, the extent of damage was similar in GALC+/- and wild-type (WT) mice. In contrast, GALC+/- mice had striking defects in repair of cuprizone-induced damage. We further found unexpected microglial defects in myelin debris clearance and in the ability to up-regulate the Trem2 microglial protein critical for debris uptake. These defects were rescued by exposure to a lysosomal re-acidifying drug discovered in our studies on KD, and which provides multiple clinically relevant benefits in the twitcher (GALC+/-) mouse model of KD. Thus, heterozygous GALC mutations cause effects on biological function that may help to understand the increased disease risk in heterozygous carriers of such mutations and to understand why GALC variations increase the risk of MS. Our findings indicate that while some genetic risk factors may contribute to complex diseases by increasing the risk of tissue damage, others may do so by compromising tissue repair.

Genome-wide association studies are identifying multiple genetic risk factors for several diseases, but the functional role of these changes remains mostly unknown. Variants in the galactocerebrosidase (GALC) gene, for example, were identified as a risk factor for Multiple Sclerosis (MS); however, the potential biological relevance of GALC variants to MS remains elusive. We found that heterozygote GALC mutant mice have reduced myelin debris clearance and diminished remyelination after a demyelinating insult. We found no histological or behavioral differences between adult wild-type and GALC +/- animals under normal conditions. Following exposure to the demyelinating agent cuprizone, however, GALC +/- animals had significantly reduced remyelination during recovery. In addition, the microglial phagocytic response and elevation of Trem2, both necessary for clearing damaged myelin, were markedly reduced in GALC +/- animals. These altered responses could be corrected in vitro by treatment with NKH-477, a compound discovered as protective in our previous studies on Krabbe disease, which is caused by mutations in both GALC alleles. Our data are the first to show remyelination defects in individuals with a single mutant GALC allele, suggesting such carriers may have increased vulnerability to myelin damage following injury or disease due to inefficient myelin debris clearance. We thus provide a potential functional link between GALC variants and increased MS susceptibility, particularly due to the failure of remyelination associated with progressive MS. Finally, this work demonstrates that genetic variants identified through genome-wide association studies may contribute significantly to complex diseases, not by driving initial symptoms, but by altering repair mechanisms.

Study objective. To compare the amount of segmental vertebral motion produced with the lateral recovery position and the HAINES technique when performed on cadavers with destabilized cervical spines. Methods. The cervical spines of 10 cadavers were surgically destabilized at the C5–C6 vertebral segment. Sensors from an electromagnetic tracking device were affixed to the vertebrae in question to monitor the amount of anterior/posterior, medial/lateral, and distraction/compression linear motion produced during the application of the two study techniques. Results. The statistical analysis of linear motion data did not reveal any significant differences between the two recovery positions. Conclusion. At this time, no single version of the recovery position can be endorsed for the spine-injured trauma patient. More research is needed to fully ascertain the safety of commonly used recovery positions.

Neurodegenerative lysosomal storage disorders (LSDs) are severe and untreatable, and mechanisms underlying cellular dysfunction are poorly understood. We found that toxic lipids relevant to three different LSDs disrupt multiple lysosomal and other cellular functions. Unbiased drug discovery revealed several structurally distinct protective compounds, approved for other uses, that prevent lysosomal and cellular toxicities of these lipids. Toxic lipids and protective agents show unexpected convergence on control of lysosomal pH and re-acidification as a critical component of toxicity and protection. In twitcher mice (a model of Krabbe disease [KD]), a central nervous system (CNS)-penetrant protective agent rescued myelin and oligodendrocyte (OL) progenitors, improved motor behavior, and extended lifespan. Our studies reveal shared principles relevant to several LSDs, in which diverse cellular and biochemical disruptions appear to be secondary to disruption of lysosomal pH regulation by specific lipids. These studies also provide novel protective strategies that confer therapeutic benefits in a mouse model of a severe LSD., Different structurally related lipids from three genetically distinct lysosomal storage disorders are sufficient to cause multiple dysfunctions that converge on disruption of lysosomal pH as a core pathogenic mechanism., Author Summary Neurodegenerative lysosomal storage disorders (LSDs) are severe and untreatable recessive genetic disorders that cause devastating damage to the nervous system. These diseases exhibit severe disruption of lysosomes (a cellular organelle that breaks down lipids and proteins) and other aspects of cell function. However, the means by which mutations cause these dysfunctions are poorly understood. By studying different lipids that accumulate in three different LSDs, we found that lipids with specific shared structures are sufficient to cause multiple lysosomal and cellular dysfunctions, including an abnormal alkalization of the lysosomal pH. We prevented all of these dysfunctions by promoting lysosomal re-acidification and discovered several drugs—already approved for other purposes—with unexpected abilities to restore lysosomal pH and rescue cells. In a genetic mouse model of a severe LSD, one of these compounds decreased tissue damage, improved quality of life, and extended survival. In contrast with previous studies on individual disorders, our study provides novel shared principles relevant to several LSDs and uncovers relevant compounds able to provide multiple benefits in a disease-relevant model in vivo.

Background A patient with a suspected cervical spine injury may be at risk for secondary neurologic injury when initially placed and repositioned to the center of the spine board. Objectives We sought to determine which centering adjustment best limits cervical spine movement and minimizes the chance for secondary injury. Methods Using five lightly embalmed cadaveric specimens with a created global instability at C5–C6, motion sensors were anchored to the anterior surface of the vertebral bodies. Three repositioning methods were used to center the cadavers on the spine board: horizontal slide, diagonal slide, and V-adjustment. An electromagnetic tracking device measured angular (degrees) and translation (millimeters) motions at the C5–C6 level during each of the three centering adjustments. The dependent variables were angular motion (flexion-extension, axial rotation, lateral flexion) and translational displacement (anteroposterior, axial, and medial-lateral). Results The nonuniform condition produced significantly less flexion-extension than the uniform condition ( p = 0.048). The horizontal slide adjustment produced less cervical flexion-extension ( p = 0.015), lateral bending ( p = 0.003), and axial rotation ( p = 0.034) than the V-adjustment. Similarly, translation was significantly less with the horizontal adjustment than with the V-adjustment; medial-lateral ( p = 0.017), axial ( p p = 0.006). Conclusions Of the three adjustments, our team found that horizontal slide was also easier to complete than the other methods. The horizontal slide best limited cervical spine motion and may be the most helpful for minimizing secondary injury based on the study findings.