The Complement Regulator Susd4 Influences Nervous-System Function and Neuronal Morphology in Mice

Abstract

The SUSD4 (Sushi domain-containing protein 4) gene encodes a complement inhibitor that is frequently deleted in 1q41q42 microdeletion syndrome, a multisystem congenital disorder that includes neurodevelopmental abnormalities. To understand SUSD4's role in the mammalian nervous system, we analyzed Susd4 knockout (KO) mice. Susd4 KO mice exhibited significant defects in motor performance and significantly higher levels of anxiety-like behaviors. Susd4 KO brain had abnormal ''hairy'' basket cells surrounding Purkinje neurons within the cerebellum and significantly reduced dendritic spine density in hippocampal pyramidal neurons. Neurons and oligodendrocyte lineage cells of wild-type mice were found to express Susd4 mRNA. Protein expression of the complement component C1q was increased in the brains of Susd4 KO mice. Our data indicate that SUSD4 plays an important role in neuronal functions, possibly via the complement pathway, and that SUSD4 deletion may contribute to the nervous system abnormalities in patients with 1q41q42 deletions.

The Role of Complement in Synaptic Pruning and Neurodegeneration

“… 2 RNA-seq of sorted brain cell types has provided strong evidence of this in the past few years, 11 although the source of several components, such as C1r, C1s, and C2, required for the cleavage of first C4, then, C2 and ultimately C3 (via a C4b2b enzyme complex), and the terminal components remain to be determined as the technology becomes optimized for sensitivity required to detect local synthesis of induced components. In addition, the continuing discovery of molecules in the brain with structures similar to some complement components and complement regulators 12–14 suggests the need for protection, regulation and repair in the brain and suggest that more novel components may yet to be uncovered.…”

The Complement System in the Central Nervous System: From Neurodevelopment to Neurodegeneration

“…Moreover, complement regulatory proteins expressed in neurons were shown to increase neuronal tolerance against complement attacks. Several novel endogenous complement inhibitors, which belong to the sushi domain family, were shown to protect neurons against excessive synapse elimination [ 106 , 107 , 173 ]. It may explain why susceptibility to complement attack varies between individuals.…”

“…Interestingly, a novel complement factor sushi domain-containing protein 4 (Susd4) has been found with abundant expression in neurons. In addition to blocking neuronal C1q expression, Susd4 also binds to C1q and C1q complex with sushi motifs to impede C3 convertase [ 106 ]. Another sushi domain protein SRPX2 also functions as an endogenous neuronal complement inhibitor, which protects neurons against synapse elimination during neurodevelopment [ 107 ].…”

SUSD4 Controls Activity-Dependent Degradation of AMPA Receptor GLUA2 and Synaptic Plasticity

“…Susd4 loss-of-function leads to motor impairments, a symptom that is also found in ASD patients (Fournier et al, 2010). Very recently, a reduction in exploratory behavior, in addition to impairments of motor coordination, was reported after Susd4 loss-of-function (Zhu et al, 2020). Long-term synaptic plasticity has been proposed as a mechanism for learning and memory.…”