Researcher Tomoko Tanaka and Project Leader Hikari Yoshikane of the Department of Basic Medical Sciences and Senior Researcher Haruo Okado, Head Researcher Shinobu Hirai, and Research Assistant Hiroko Shimbo of the Department of Psychiatry and Behavioral Sciences at the Tokyo Metropolitan Institute of Medical Science (TMiMS), and their colleagues have shown the development of early age-related decline in spatial cognition and its prevention with minocycline in Rp58 heterozygous-knockout mice, a mouse model of ZBTB18/RP58 haploinsufficiency-associated intellectual disability (haploinsufficiency: the situation when one copy of a gene is either inactivated or deleted, and the remaining functional copy cannot produce enough of the gene product to maintain normal function). The findings are expected to contribute to the elucidation of pathogenic mechanisms of, and development of, preventive and therapeutic means for RP58/ZBTB18 haploinsufficiency as well as to the prevention of age-related cognitive decline. The study was published in the Journal of Neuroinflammation.
Genome analysis of patients with intellectual disability has revealed many truncated variants and nonsense and missense mutations in the RP58 gene, and haploinsufficiency of RP58 is known to cause intellectual disability. RP58 is highly expressed in the neonatal brain, and its expression continues after brain maturation in glutamatergic neurons of the cerebral cortex. Therefore, it is important to establish a treatment strategy for RP58 haploinsufficiency-associated intellectual disability.
The research group has previously generated Rp58 conventional and conditional knockout mice and shown that Rp58 is crucial in the formation of the cerebral cortex. They also have shown that Rp58 heterozygous-knockout mice can serve as a model for human RP58 haploinsufficiency-associated intellectual disability. However, it is unknown why RP58 aberrations cause intellectual disability.
Meanwhile, patients with intellectual disabilities are prone to dementia. Thus, in this study, the research group focused on the development of cognitive dysfunction during adulthood using intellectual disability model mice (Rp58 heterozygous-knockout mice). The results showed that Rp58 heterozygous-knockout mice exhibited accelerated age-related impairment in spatial cognition, suggesting that these mice may serve as a model for early onset dementia associated with intellectual disability. Rp58 heterozygous-knockout mice also exhibited defective DNA repair in hippocampal mossy cells, early accumulation of DNA damage, and microglial inflammatory reactions in the hippocampus, suggesting that the age-related cognitive impairment in RP58 haploinsufficiency is caused by chronic inflammation associated with defective DNA repair.
The central nervous system is particularly susceptible to DNA damage repair defects, and unrepaired DNA damage is known to cause various neurodevelopmental and neurodegenerative disorders, including intellectual disability. Therefore, therapies targeting DNA damage and inflammation may be effective for pathological conditions associated with RP58 haploinsufficiency. Furthermore, minocycline, which has neuroprotective and anti-inflammatory effects, successfully attenuated the phenotype associated with premature aging in Rp58 heterozygous-knockout mice.
Journal Information
Publication: Journal of Neuroinflammation
Title: Minocycline prevents early age-related cognitive decline in a mouse model of intellectual disability caused by ZBTB18/RP58 haploinsufficiency
DOI: 10.1186/s12974-024-03217-1
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