The endogenous neuronal complement inhibitor SRPX2 protects against complement-mediated synapse elimination during development

Cong, Qifei; Soteros, Breeanne M.; Wollet, Mackenna; Kim, Jun Hee; Sia, Gek Ming

doi:10.1038/s41593-020-0672-0

Cited by 87 publications

(92 citation statements)

References 59 publications

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“…Mutations in this X-linked SRPX2 are associated with language disorders. Sia and colleagues recently extended these studies to demonstrated that this protein inhibits complement-dependent synapse pruning during postnatal development with region-and synapse-type specificity [7]. Understanding the molecular basis for the induction of expression and the inhibitory specificity of these newly uncovered families of proteins in the brain may provide pathways to precision therapeutics to control synaptic vulnerability to elimination.…”

Section: Regulators Of Complementmentioning

confidence: 99%

“…This is normally avoided by a number of circulating (C1 inhibitor, factor H, C4b-binding protein) and membraneassociated (CD46, CD55, CR1, CD59) complement regulators [6]. More recently, novel complement control proteins are being discovered, often with tissue-specific expression ( [7] and reviewed in [8]), although the domain protein structures have similar features [9]. The impact that the complement system has on human health and disease has become even more evident with the recognition that combinations of specific complement component genetic polymorphisms, collectively referred to as a "complotype" [10] confer differential sensitivity to infection and autoimmunity.…”

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confidence: 99%

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The good, the bad, and the opportunities of the complement system in neurodegenerative disease

Schartz

Tenner

2020

J Neuroinflammation

182

183

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The complement cascade is a critical effector mechanism of the innate immune system that contributes to the rapid clearance of pathogens and dead or dying cells, as well as contributing to the extent and limit of the inflammatory immune response. In addition, some of the early components of this cascade have been clearly shown to play a beneficial role in synapse elimination during the development of the nervous system, although excessive complement-mediated synaptic pruning in the adult or injured brain may be detrimental in multiple neurogenerative disorders. While many of these later studies have been in mouse models, observations consistent with this notion have been reported in human postmortem examination of brain tissue. Increasing awareness of distinct roles of C1q, the initial recognition component of the classical complement pathway, that are independent of the rest of the complement cascade, as well as the relationship with other signaling pathways of inflammation (in the periphery as well as the central nervous system), highlights the need for a thorough understanding of these molecular entities and pathways to facilitate successful therapeutic design, including target identification, disease stage for treatment, and delivery in specific neurologic disorders. Here, we review the evidence for both beneficial and detrimental effects of complement components and activation products in multiple neurodegenerative disorders. Evidence for requisite co-factors for the diverse consequences are reviewed, as well as the recent studies that support the possibility of successful pharmacological approaches to suppress excessive and detrimental complement-mediated chronic inflammation, while preserving beneficial effects of complement components, to slow the progression of neurodegenerative disease.

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Section: Regulators Of Complementmentioning

confidence: 99%

mentioning

confidence: 99%

The good, the bad, and the opportunities of the complement system in neurodegenerative disease

Schartz

Tenner

2020

J Neuroinflammation

182

183

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“…spines with heads vs. without heads (Gunnersen et al, 2007). Three sushi-domaincontaining proteins, Susd2, Sez-6 (as above), and Srpx2 have been shown to regulate excitatory synapse number in culture and/or in vivo in mouse (Gunnersen et al, 2007;Nadjar et al, 2015;Sia et al, 2013;Soteros et al, 2018); evidence for a connection with the complement cascade and pruning has recently been presented for Srpx2 (Cong et al, 2020) but has not been investigated for the other sushi-domain containing proteins. Among these, only CSMD1 has been consistently associated with schizophrenia to date.…”

Section: A Broader Landscape Of Neural Complement Regulationmentioning

confidence: 99%

CUB and Sushi Multiple Domains 1 (CSMD1) opposes the complement cascade in neural tissues

Baum

Wilton

Muthukumar

et al. 2020

Preprint

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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.

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“…While the classical complement cascade is used to eliminate synapses, inhibition of the complement cascade can protect synapses against removal. Sushi domain protein SRPX2 is shown to bind directly to C1q, preventing the initiation and activation of the complement cascade, thereby preventing complementmediated synapse elimination (Cong, Soteros, Wollet, Kim, & Sia, 2020). Microglia production of C1q and C3 and regulation of lysosomal function are mediated by expression of progranulin.…”

Section: Microglia Shape Neural Circuitry By Pruning Synapsesmentioning

confidence: 99%

Axon growth and synaptic function: A balancing act for axonal regeneration and neuronal circuit formation in CNS trauma and disease

Kiyoshi

Tedeschi

2020

Developmental Neurobiology

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Axon regeneration failure following central nervous system (CNS) trauma and disease often leads to permanent functional disability. Promoting axon sprouting and regeneration of spared and injured axons as well as refinement of existing or de novo formation of neuronal circuits can attain neurological recovery (Hutson & Di Giovanni, 2019; Maier & Schwab, 2006). The development of neuronal circuits in the mammalian CNS is a dynamic process that requires coordinated epigenetic regulation of gene expression (Henikoff, 2008; Jaenisch & Bird, 2003). Genome-wide remodeling of the epigenetic landscape allows axon elongation, membrane expansion and navigation toward target areas as well as axon branching, synapse formation, and refinement to be spatially and temporally ordered (Kolodkin & Tessier

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The endogenous neuronal complement inhibitor SRPX2 protects against complement-mediated synapse elimination during development

Cited by 87 publications

References 59 publications

The good, the bad, and the opportunities of the complement system in neurodegenerative disease

The good, the bad, and the opportunities of the complement system in neurodegenerative disease

CUB and Sushi Multiple Domains 1 (CSMD1) opposes the complement cascade in neural tissues

Axon growth and synaptic function: A balancing act for axonal regeneration and neuronal circuit formation in CNS trauma and disease

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