Deficiency of aminopeptidase P1 causes behavioral hyperactivity, cognitive deficits, and hippocampal neurodegeneration

Bae, Young Soo; Yoon, Sang Ho; Han, Ji Yeon; Woo, Jooyeon; Cho, Yi Sul; Kwon, Seok-Kyu; Bae, Yong-Chul; Kim, Daesoo; Kim, Eunjoon; Kim, Myoung-Hwan

doi:10.1111/gbb.12419

Cited by 11 publications

(14 citation statements)

References 43 publications

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“…6d-g). This finding is consistent with the neuropathology of Xpnpep1 −/− mice in that neurodegeneration was exclusively observed in the CA3 subfield 8 . In addition, some microglia were present but did not accumulate around vacuoles in the CA3 area of Xpnpep1 −/− mice ( Fig.…”

Section: Deficiency Of Aminopeptidase P1 Modifies the Population Of Gsupporting

confidence: 90%

“…Intriguingly, mice with the iDG phenotype exhibit hyperexcitability of the dentate GCs. The existence of developmental retardation, hyperlocomotion, and impaired hippocampus-dependent learning in Xpnpep1 −/− mice 7,8 means it is likely that iDG, in addition to the hyperexcitable CA3 pyramidal neurons, contributes to hippocampal dysfunction. However, the excitability of Xpnpep1 −/− GCs requires further investigation.…”

Section: Discussionmentioning

confidence: 99%

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Altered hippocampal gene expression, glial cell population, and neuronal excitability in aminopeptidase P1 deficiency

Yoon

Bae

et al. 2021

Sci Rep

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Inborn errors of metabolism are often associated with neurodevelopmental disorders and brain injury. A deficiency of aminopeptidase P1, a proline-specific endopeptidase encoded by the Xpnpep1 gene, causes neurological complications in both humans and mice. In addition, aminopeptidase P1-deficient mice exhibit hippocampal neurodegeneration and impaired hippocampus-dependent learning and memory. However, the molecular and cellular changes associated with hippocampal pathology in aminopeptidase P1 deficiency are unclear. We show here that a deficiency of aminopeptidase P1 modifies the glial population and neuronal excitability in the hippocampus. Microarray and real-time quantitative reverse transcription-polymerase chain reaction analyses identified 14 differentially expressed genes (Casp1, Ccnd1, Myoc, Opalin, Aldh1a2, Aspa, Spp1, Gstm6, Serpinb1a, Pdlim1, Dsp, Tnfaip6, Slc6a20a, Slc22a2) in the Xpnpep1−/− hippocampus. In the hippocampus, aminopeptidase P1-expression signals were mainly detected in neurons. However, deficiency of aminopeptidase P1 resulted in fewer hippocampal astrocytes and increased density of microglia in the hippocampal CA3 area. In addition, Xpnpep1−/− CA3b pyramidal neurons were more excitable than wild-type neurons. These results indicate that insufficient astrocytic neuroprotection and enhanced neuronal excitability may underlie neurodegeneration and hippocampal dysfunction in aminopeptidase P1 deficiency.

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Section: Deficiency Of Aminopeptidase P1 Modifies the Population Of Gsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Altered hippocampal gene expression, glial cell population, and neuronal excitability in aminopeptidase P1 deficiency

Yoon

Bae

et al. 2021

Sci Rep

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“…ASPM is a major determinant of the size of the cerebral cortex in mammals 36,37 that plays a key role in memory, attention, perception and awareness. Knockdown of XPNPEP1, which encodes an important downstream regulator of the stress response 38 , in mice results in enhanced locomotor activity and impaired contextual fear memory 39 . An emerging theme in equine transcriptomics and genomics research suggests a link between the exercise phenotype and behavioural plasticity.…”

Section: Scientific Reports |mentioning

confidence: 99%

Genomic inbreeding trends, influential sire lines and selection in the global Thoroughbred horse population

McGivney

Han

Corduff

et al. 2020

Sci Rep

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The Thoroughbred horse is a highly valued domestic animal population under strong selection for athletic phenotypes. Here we present a high resolution genomics-based analysis of inbreeding in the population that may form the basis for evidence-based discussion amid concerns in the breeding industry over the increasing use of small numbers of popular sire lines, which may accelerate a loss of genetic diversity. In the most comprehensive globally representative sample of Thoroughbreds to-date (n = 10,118), including prominent stallions (n = 305) from the major bloodstock regions of the world, we show using pan-genomic SNP genotypes that there has been a highly significant decline in global genetic diversity during the last five decades (F iS R 2 = 0.942, P = 2.19 × 10 −13 ; F RoH R 2 = 0.88, P = 1.81 × 10 −10 ) that has likely been influenced by the use of popular sire lines. Estimates of effective population size in the global and regional populations indicate that there is some level of regional variation that may be exploited to improve global genetic diversity. Inbreeding is often a consequence of selection, which in managed animal populations tends to be driven by preferences for cultural, aesthetic or economically advantageous phenotypes. Using a composite selection signals approach, we show that centuries of selection for favourable athletic traits among Thoroughbreds acts on genes with functions in behaviour, musculoskeletal conformation and metabolism. As well as classical selective sweeps at core loci, polygenic adaptation for functional modalities in cardiovascular signalling, organismal growth and development, cellular stress and injury, metabolic pathways and neurotransmitters and other nervous system signalling has shaped the Thoroughbred athletic phenotype. Our results demonstrate that genomics-based approaches to identify genetic outcrosses will add valuable objectivity to augment traditional methods of stallion selection and that genomicsbased methods will be beneficial to actively monitor the population to address the marked inbreeding trend.The Thoroughbred is among the fastest animals selected by humans for sport, originating from "the commingled blood of Arabs, Turks and Barbs" 1 crossed with local British and Irish mares 2 "but selection and training have together made him a very different animal from his parent-stocks" 1 . The Thoroughbred is now a large (N ~ 500,000) global breed but, in the context of modern horse breeds, it has very low genetic diversity 3,4 due to the limited foundation alleles at the establishment of the stud book and restriction of external gene flow subsequent to the closing of the population 5-7 . In Thoroughbred horse breeding selection of potential champion racehorses is a global multi-billion-dollar business, but there is no systematic industry-mediated genomic selection or genetic population management. We hypothesised that the market-driven emphasis on highly valuable pedigrees and the common practice of inbreeding to successful ancestors in attempts to reinforce...

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“…ASPM is a major determinant of the size of the cerebral cortex in mammals [36, 65] that plays a key role in memory, attention, perception and awareness. Knockdown of XPNPEP1 , which encodes an important downstream regulator of the stress response [38], in mice results in enhanced locomotor activity and impaired contextual fear memory [39]. An emerging theme in equine transcriptomics and genomics research suggests a link between the exercise phenotype and behavioural plasticity.…”

Section: Resultsmentioning

confidence: 99%

Genomic inbreeding trends in the global Thoroughbred horse population driven by influential sire lines and selection for exercise trait-related genes

et al. 2019

Preprint

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13The Thoroughbred horse is a highly valued domestic animal population under strong 14 selection for athletic phenotypes. Here we present a high resolution genomics-based analysis of 15 inbreeding in the population that may form the basis for evidence-based discussion amid concerns 16 in the breeding industry over the increasing use of small numbers of popular sire lines, which 17 may accelerate a loss of genetic diversity. In the most comprehensive globally representative 18 sample of Thoroughbreds to-date (n = 10,118), including prominent stallions (n = 305) from the 19 major bloodstock regions of the world, we show using pan-genomic SNP genotypes that there has 20 been a highly significant decline in global genetic diversity during the last five decades (FIS R 2 = 21 0.942, P = 2.19 × 10 -13 ; FROH R 2 = 0.88, P = 1.81 × 10 -10 ) that has likely been influenced by the use 22 of popular sire lines. Estimates of effective population size in the global and regional populations 23 indicate that there is some level of regional variation that may be exploited to improve global 24 genetic diversity. Inbreeding is often a consequence of selection, which in managed animal 25 populations tends to be driven by preferences for cultural, aesthetic or economically 26 advantageous phenotypes. Using a composite selection signals approach, we show that centuries 27 of selection for favourable athletic traits among Thoroughbreds acts on genes with functions in 28 behaviour, musculoskeletal conformation and metabolism. As well as classical selective sweeps at 29 core loci, polygenic adaptation for functional modalities in cardiovascular signalling, organismal 30 growth and development, cellular stress and injury, metabolic pathways and neurotransmitters 31 and other nervous system signalling has shaped the Thoroughbred athletic phenotype. Our 32 results demonstrate that genomics-based approaches to identify genetic outcrosses will add 33 valuable objectivity to augment traditional methods of stallion selection and that genomics-based 34 methods will be beneficial to actively monitor the population to address the marked inbreeding 35 trend. 36 Author Summary 37In the highly valuable global Thoroughbred horse industry, there is no systematic industry-38 mediated genetic population management. Purposeful inbreeding is common practice and there is an 39 increasing use of popular sires. Inbreeding can lead to population health and fertility decline, but there 40 is little objective genomics-based data for the Thoroughbred to catalyse action and support changes in 41 breeding practices. Here, we describe the most comprehensive genetic analysis in the population among 42 10,000 Thoroughbreds from the major bloodstock regions of the world and reveal a highly significant 43 increase in inbreeding during the last five decades. The main drivers of genetic diversity are the most 44 influential 'breed-shaping' sire lines, Sadler's Wells, Danehill and A.P. Indy. We identified genomic 45 regions subject to positive selection containing genes f...

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Deficiency of aminopeptidase P1 causes behavioral hyperactivity, cognitive deficits, and hippocampal neurodegeneration

Cited by 11 publications

References 43 publications

Altered hippocampal gene expression, glial cell population, and neuronal excitability in aminopeptidase P1 deficiency

Altered hippocampal gene expression, glial cell population, and neuronal excitability in aminopeptidase P1 deficiency

Genomic inbreeding trends, influential sire lines and selection in the global Thoroughbred horse population

Genomic inbreeding trends in the global Thoroughbred horse population driven by influential sire lines and selection for exercise trait-related genes

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