Interactions between knockout of schizophrenia risk factor Dysbindin-1 and copper metabolism in mice

Schoonover, Kirsten E.; McMeekin, Laura J.; Farmer, Charlene B.; Varghese, Neelu E; Queern, Stacy L.; Lapi, Suzanne E.; Cowell, Rita M.; Roberts, Rosalinda C.

doi:10.1016/j.brainresbull.2020.07.024

Cited by 6 publications

(3 citation statements)

References 98 publications

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“…Intriguingly, protein damage accumulated to particularly high levels in brain cytosol fractions from Pcmt1 −/− mice (Kim et al , 1997; Lowenson et al , 2001). We therefore proceeded to test the ability of isoDGR‐specific immunotherapy to preserve motor and cognitive functions in Pcmt1 −/− mice by using clasping and ledge behavior tests (Cahill et al , 2019; Schoonover et al , 2020; Castillo‐Mariqueo & Giménez‐Llort, 2022). Six‐week‐old Pcmt1 +/+ and Pcmt1 +/− mice displayed normal extension reflex in the hind‐limbs and used body torsion when suspended in the air.…”

Section: Resultsmentioning

confidence: 99%

Immunotherapy targeting isoDGR‐protein damage extends lifespan in a mouse model of protein deamidation

Kalailingam,

Mohd‐Kahliab,

Ngan

et al. 2023

EMBO Mol Med

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Aging results from the accumulation of molecular damage that impairs normal biochemical processes. We previously reported that age‐linked damage to amino acid sequence NGR (Asn‐Gly‐Arg) results in “gain‐of‐function” conformational switching to isoDGR (isoAsp‐Gly‐Arg). This integrin‐binding motif activates leukocytes and promotes chronic inflammation, which are characteristic features of age‐linked cardiovascular disorders. We now report that anti‐isoDGR immunotherapy mitigates lifespan reduction of Pcmt1−/− mouse. We observed extensive accumulation of isoDGR and inflammatory cytokine expression in multiple tissues from Pcmt1−/− and naturally aged WT animals, which could also be induced via injection of isoDGR‐modified plasma proteins or synthetic peptides into young WT animals. However, weekly injection of anti‐isoDGR mAb (1 mg/kg) was sufficient to significantly reduce isoDGR‐protein levels in body tissues, decreased pro‐inflammatory cytokine concentrations in blood plasma, improved cognition/coordination metrics, and extended the average lifespan of Pcmt1−/− mice. Mechanistically, isoDGR‐mAb mediated immune clearance of damaged isoDGR‐proteins via antibody‐dependent cellular phagocytosis (ADCP). These results indicate that immunotherapy targeting age‐linked protein damage may represent an effective intervention strategy in a range of human degenerative disorders.

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Section: Resultsmentioning

confidence: 99%

Immunotherapy targeting isoDGR‐protein damage extends lifespan in a mouse model of protein deamidation

Kalailingam,

Mohd‐Kahliab,

Ngan

et al. 2023

EMBO Mol Med

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“…14,39 We therefore proceeded to test the ability of isoDGR-specific immunotherapy to preserve motor and cognitive function in Pcmt1 -/mice using clasping and ledge behaviour tests. [40][41][42] Six-week-old PCMT1 +/+ and Pcmt1 +/mice displayed normal extension reflex in the hind-limbs and used body torsion when suspended in the air. In contrast, Pcmt1 -/mice exhibited severe hind-limb clasping and high dysfunction scores than were improved upon treatment with isoDGR-specific mAb (Fig.…”

Section: Isodgr-specific Antibody Therapy Improves Motor Function Of ...mentioning

confidence: 99%

Antibody targeting of aging damaged isoDGR-proteins doubles lifespan in a mouse model of chronic inflammation

Kalailingam

Mohd-Kahliab

Ngan

et al. 2023

Preprint

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Aging is the result of the accumulation of molecular damages that impair normal biochemical activities. We previously reported that aging-damaged amino acid sequence NGR (Asn-Gly-Arg) results in a gain-of-function conformational switching to isoDGR (isoAsp-Gly-Arg) motif. This integrin-binding motif activates leukocytes to induce chronic inflammation, which are characteristic features of age-linked cardiovascular disorders. We now report that anti-isoDGR immunotherapy doubles lifespan in mouse model of chronic inflammation. We observed extensive accumulation of isoDGR and inflammatory cytokine expression in multiple tissues from Pcmt1-KO and old WT animals, which could also be induced via injection of isoDGR-modified plasma proteins or synthetic peptides into young WT animals. However, weekly injection of anti-isoDGR mAb (1mg/kg) was sufficient to significantly reduce isoDGR-modified proteins and pro-inflammatory cytokine expression, improve behaviour and coordination, and double the average lifespan of Pcmt1-KO mice. Mechanistically, isoDGR-mAb mediated the immune clearance of damaged isoDGR-proteins by antibody-dependent cellular phagocytosis. These results indicate that immunotherapy targeting aging-damaged proteins may represent effective interventions for a range of age-linked degenerative disorders.

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“…Following this impairment, the subject’s cognitive deficits will be severe. In addition to glutamate transmission, abrogation of dysbindin-1 functions acts as a chain reaction that also leads to impairment of copper transport [ 57 , 58 , 59 , 60 ]. Affecting the latter will generate a deficiency of this metal, crucial for cell homeostasis.…”

Section: Geneticsmentioning

confidence: 99%

Genetic polymorphism and neuroanatomical changes in schizophrenia

Năstase

Vlaicu²,

Trifu³

2022

Rom J Morphol Embryol

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The article is a review of the latest meta-analyses regarding the genetic spectrum in schizophrenia, discussing the risks given by the disruptedin-schizophrenia 1 (DISC1), catechol-O-methyltransferase (COMT), monoamine oxidases-A/B (MAO-A/B), glutamic acid decarboxylase 67 (GAD67) and neuregulin 1 (NRG1) genes, and dysbindin-1 protein. The DISC1 polymorphism significantly increases the risk of schizophrenia, as well injuries from the prefrontal cortex that affect connectivity. NRG1 is one of the most important proteins involved. Its polymorphism is associated with the reduction of areas in the corpus callosum, right uncinate, inferior lateral fronto-occipital fascicle, right external capsule, fornix, right optic tract, gyrus. NRG1 and the ErbB4 receptor (tyrosine kinase receptor) are closely related to the N-methyl-D-aspartate receptor (NMDAR) (glutamate receptor). COMT is located on chromosome 22 and together with interleukin-10 (IL-10) have an anti-inflammatory and immunosuppressive function that influences the dopaminergic system. MAO gene methylation has been associated with mental disorders. MAO-A is a risk gene in the onset of schizophrenia, more precisely a certain type of single-nucleotide polymorphism (SNP), at the gene level, is associated with schizophrenia. In schizophrenia, we find deficits of the γ-aminobutyric acid (GABA)ergic neurotransmitter, the dysfunctions being found predominantly at the level of the substantia nigra. In schizophrenia, missing an allele at GAD67, caused by a SNP, has been correlated with decreases in parvalbumin (PV), somatostatin receptor (SSR), and GAD ribonucleic acid (RNA). Resulting in the inability to mature PV and SSR neurons, which has been associated with hyperactivity.

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Interactions between knockout of schizophrenia risk factor Dysbindin-1 and copper metabolism in mice

Cited by 6 publications

References 98 publications

Immunotherapy targeting isoDGR‐protein damage extends lifespan in a mouse model of protein deamidation

Immunotherapy targeting isoDGR‐protein damage extends lifespan in a mouse model of protein deamidation

Antibody targeting of aging damaged isoDGR-proteins doubles lifespan in a mouse model of chronic inflammation

Genetic polymorphism and neuroanatomical changes in schizophrenia

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