Ndufs4 ablation decreases synaptophysin expression in hippocampus

Shil, Subrata Kumar; Kagawa, Yoshiteru; Umaru, Banlanjo Abdulaziz; Nanto-Hara, Fumika; Miyazaki, Hirofumi; Yamamoto, Yoshiyuki; Kobayashi, Shuhei; Suzuki, Chitose; Abe, Takaaki; Owada, Yuji

doi:10.1038/s41598-021-90127-4

Cited by 8 publications

(6 citation statements)

References 53 publications

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“…Ndufs4 KO mice present with a characteristic fatal encephalopathy in which neurodegeneration and neuroinflammation occur in specific brain regions. These two processes are mainly observed in the VN, OB, brainstem, cerebellum, and hippocampus (Johnson et al, 2013; Miller et al, 2020; Quintana et al, 2010; Shil et al, 2021). This neurodegenerative and neuroinflammatory process is the main cause of the Ndufs4 KO phenotype since brain‐specific NDUFS4 deficiency (using Nes‐Cre mice) results in an almost identical phenotype to that of systemic Ndufs4 KO (Quintana et al, 2010).…”

Section: Resultsmentioning

confidence: 99%

Microglial response promotes neurodegeneration in the Ndufs4 KO mouse model of Leigh syndrome

Aguilar

Comes

Canal

et al. 2022

Glia

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Leigh syndrome is a mitochondrial disease characterized by neurodegeneration, neuroinflammation, and early death. Mice lacking NDUFS4, a mitochondrial complex I subunit (Ndufs4 KO mice), have been established as a good animal model for studying human pathology associated with Leigh syndrome. As the disease progresses, there is an increase in neurodegeneration and neuroinflammation, thereby leading to deteriorating neurological symptoms, including motor deficits, breathing alterations, and eventually, death of the animal. However, despite the magnitude of neuroinflammation associated with brain lesions, the role of neuroinflammatory pathways and their main cellular components have not been addressed directly as relevant players in the disease pathology. Here, we investigate the role of microglial cells, the main immune cells of the CNS, in Leigh-like syndrome pathology, by pharmacologically depleting them using the colony-stimulating factor 1 receptor antagonist PLX3397. Microglial depletion extended lifespan and delayed motor symptoms in Ndufs4 KO mice, likely by preventing neuronal loss. Next, we investigated the role of the major cytokine interleukin-6 (IL-6) in the disease progression. IL-6 deficiency partially rescued breathing abnormalities and modulated gliosis but did not extend the lifespan or rescue motor decline in Ndufs4 KO mice. The present results show that microglial accumulation is pathogenic, in a process independent of IL-6, and hints toward a contributing role of neuroinflammation in the disease of Ndufs4 KO mice and potentially in patients with Leigh syndrome.

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Section: Resultsmentioning

confidence: 99%

Microglial response promotes neurodegeneration in the Ndufs4 KO mouse model of Leigh syndrome

Aguilar

Comes

Canal

et al. 2022

Glia

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“…Upon gene set category enrichment analysis, we find that many of these genes that are deemed ‘outliers’ are related to functions in development, transcription, nervous system development, neurogenesis, and metabolism. For example, the chimpanzee PFC shows a significant upregulation in genes involved in energy storage and transfer, such as ETFA and NDUFS4, which are both involved in electron transport for ATP generation, as well as ANKH, implicated in phosphate transport ( Szeri et al, 2020 ; Henriques et al, 2021 ; Shil et al, 2021 ) We also see that the chimpanzee PFC shows unique expression patterns in genes related to synaptic activity and neurotransmitter release, including significant downregulation of GABRA4 and SYN1 ( Fassio et al, 2011 ; Fan et al, 2020 Fan et al, 2020 ; Fassio et al, 2011 ). In contrast, the human CBL and PFC both display a significant upregulation of genes related to Amyloid protein production (APP), a major component of many neurodegenerative diseases with functions in synaptic signaling ( O’Brien and Wong, 2011 ).…”

Section: Resultsmentioning

confidence: 86%

Tempo and mode of gene expression evolution in the brain across primates

Rickelton,

Zintel,

Pizzollo

et al. 2024

eLife

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Primate evolution has led to a remarkable diversity of behavioral specializations and pronounced brain size variation among species (Barton, 2012; DeCasien & Higham, 2019; Powell, Isler, & Barton, 2017). Gene expression provides a promising opportunity for studying the molecular basis of brain evolution, but it has been explored in very few primate species to date (e.g. Khaitovich et al., 2005; Khrameeva et al., 2020; Ma et al., 2022; Somel et al., 2009). To understand the landscape of gene expression evolution across the primate lineage, we generated and analyzed RNA-Seq data from four brain regions in an unprecedented eighteen species. Here we show a remarkable level of variation in gene expression among hominid species, including humans and chimpanzees, despite their relatively recent divergence time from other primates. We found that individual genes display a wide range of expression dynamics across evolutionary time reflective of the diverse selection pressures acting on genes within primate brain tissue. Using our samples that represents a 190-fold difference in primate brain size, we identified genes with variation in expression most correlated with brain size. Our study extensively broadens the phylogenetic context of what is known about the molecular evolution of the brain across primates and identifies novel candidate genes for study of genetic regulation of brain evolution.

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“…One study found that NDUFS4 silencing led to significantly decreased expression of synaptophysin, a pre‐synaptic protein. This was further found to lead to shorter neurite lengths and suggested a role for NDUFS4‐modulated mitochondrial activity in neuroplasticity 42 . An important factor for adequate development and remodelling of synapses is protein synthesis, another energy demanding process dependent on mitochondrial function.…”

Section: Discussionmentioning

confidence: 93%

“…This was further found to lead to shorter neurite lengths and suggested a role for NDUFS4-modulated mitochondrial activity in neuroplasticity. 42 An important factor for adequate development and remodelling of synapses is protein synthesis, another energy demanding process dependent on mitochondrial function. Further, the anti-apoptotic factor BCL-X L (B-cell lymphoma extra-large) has been shown to drive presynaptic maturation via increased activity of dynamin related protein 1 (encoded by DNM1L), a protein needed for mitochondrial fission and thereby mitochondrial activity in the presynaptic terminal.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic analyses reveal neuronal specificity of Leigh syndrome associated genes

Wahedi

Soondram

Murphy

et al. 2022

J of Inher Metab Disea

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Leigh syndrome is a rare, inherited, complex neurometabolic disorder with genetic and clinical heterogeneity. Features present in affected patients range from classical stepwise developmental regression to ataxia, seizures, tremor, and occasionally psychiatric manifestations. Currently, more than 100 monogenic causes of Leigh syndrome have been identified, yet the pathophysiology remains unknown. Here, we sought to determine the cellular specificity within the brain of all genes currently associated with Leigh syndrome. Further, we aimed to investigate potential genetic commonalities between Leigh syndrome and other disorders with overlapping clinical features. Enrichment of our target genes within the brain was evaluated with co-expression (CoExp) network analyses constructed using existing UK Brain Expression Consortium data. To determine the cellular specificity of the Leigh associated genes, we employed expression weighted cell type enrichment (EWCE) analysis of single-cell RNA-Seq data. Finally, CoExp network modules demonstrating enrichment of Leigh syndrome associated genes were then utilised for synaptic gene ontology analysis and heritability analysis. CoExp network analyses revealed that Leigh syndrome associated genes exhibit the highest levels of expression in brain regions most affected on MRI in affected patients. EWCE revealed significant enrichment of target genes in hippocampal and somatosensory pyramidal neurons and interneurons of the brain. Analysis of CoExp modules enriched with our target genes revealed preferential association with pre-synaptic structures. Heritability studies suggested some common enrichment between Leigh syndrome and Parkinson disease and epilepsy. Our findings suggest a primary mitochondrial dysfunction as the underlying basis of Leigh syndrome, with associated genes primarily expressed in neuronal cells.

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Ndufs4 ablation decreases synaptophysin expression in hippocampus

Cited by 8 publications

References 53 publications

Microglial response promotes neurodegeneration in the Ndufs4 KO mouse model of Leigh syndrome

Microglial response promotes neurodegeneration in the Ndufs4 KO mouse model of Leigh syndrome

Tempo and mode of gene expression evolution in the brain across primates

Transcriptomic analyses reveal neuronal specificity of Leigh syndrome associated genes

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