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GGC repeat expansion within NOTCH2NLC causes behavioral deficits and neurodegeneration through misregulated alternative splicing

ABSTRACT: GGC repeat expansion within NOTCH2NLC causes behavioral deficits and neurodegeneration through misregulated alternative splicing

PROVIDER: PRJNA758104 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15632744_1.fastq.gz	Fastqsanger.gz
	SRR15632744_2.fastq.gz	Fastqsanger.gz
	SRR15632745_1.fastq.gz	Fastqsanger.gz
	SRR15632745_2.fastq.gz	Fastqsanger.gz
	SRR15632746_1.fastq.gz	Fastqsanger.gz

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GGC repeat expansion within NOTCH2NLC causes behavioral deficits and neurodegeneration through misregulated alternative splicing

Project description:GGC repeat expansion within NOTCH2NLC gene has been identified as the genetic cause of neuronal intranuclear inclusion disease (NIID). To understand the molecular pathogenesis of NIID, here we have established both a transgenic mouse model and a human neural progenitor cell (hNPC) model. We show that the expression of the NOTCH2NLC gene with expanded GGC repeats produces multiple forms of polypeptides, including polyglycine (polyG), polyalanine (polyA) and polyarginine (polyR), and leads to widespread intranuclear inclusions, severe neurodegeneration, motor dysfunction and cognitive deficits, which faithfully mimics the clinical manifestations and pathological features associated with NIID. We further performed RNA-seq on the prefrontal cortex, cerebellum and hippocampus of the transgenic mice and on the hNPC model and identified a large proportion of conserved alternative splicing between the NIID mouse and hNPC cell models. Analyses of the conserved alternative splicing revealed the enrichment of the binding motif of hnRNPM. We found that hnRNPM could interact with and be sequestered by expanded NOTCH2NLC-polyG and -polyA. Functional expression of hnRNPM could ameliorate the cellular toxicity caused by expanded GGC repeats within NOTCH2NLC. These results together suggest that dysregulated alternative splicing could play a vital role in the molecular pathogenesis of NIID.

2023-01-04 | GSE182878 | GEO

Partial depletion of SRSF1 rescued the C9ORF72-repeat neurodegeneration-associated locomotor deficits in G4C2x36 Drosophila lines

Project description:Partial depletion of SRSF1 rescued the C9ORF72-repeat neurodegeneration-associated locomotor deficits in G4C2x36 Drosophila lines

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Impairment of methylglyoxal detoxification systems causes mitochondrial dysfunction and behavioral deficits

Project description:Methylglyoxal (MG) is a reactive alpha-dicarbonyl by-product of glycolysis. Several bio-defense systems to detoxify the highly toxic MG are equipped in our body, including an enzymatic system by glyoxalase (GLO) 1 and GLO2 and a scavenge system by vitamin B6 (VB6). We have reported that some population of patients with schizophrenia shows impairment of the MG detoxification systems. Although we have evidences showing a link between impairment of MG detoxification systems and development of schizophrenia, the molecular mechanism to connect them remains poorly understood. Here, we generated a novel mouse model for MG detoxification deficits by feeding Glo1 knockout mice with VB6-lacking diets (KO/VB6(-)), and evaluate effects of impaired MG detoxification systems on brain function. KO/VB6(-) mice showed the accumulation of MG in the prefrontal cortex (PFC), hippocampus, and striatum, and displayed schizophrenia-like behavioral deficits, such as social deficits, cognitive impairment, a sensorimotor deficit in the prepulse inhibition test. Furthermore, we found aberrant gene expression related to mitochondria function in the PFC of the KO/VB6(-) mice by RNA-seq and weighted gene correlation network analysis (WGCNA). Finally, we actually demonstrated respiratory deficits in mitochondria isolated from the PFC of KO/VB6(-) mice. These findings suggest that MG detoxification deficits might cause schizophrenia-like behavioral deficits via mitochondrial dysfunction in the PFC.

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Impairment of methylglyoxal detoxification systems causes mitochondrial dysfunction and behavioral deficits

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Neuronal APOE4 removal strongly protects against Tau-mediated gliosis, neurodegeneration, and myelin deficits

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Long-term caffeine treatment of Alzheimer mouse models ameliorates behavioural deficits and neuron loss and promotes cellular and molecular markers of neurogenesis

Project description:Epidemiological studies suggest that consumption of caffeine, the most commonly consumed psychoactive substances found in coffee, tea or soft drinks reduces the risk of developing Alzheimer’s disease (AD). While previous studies employing transgenic AD mouse models reported on reduced amyloid plaque load or an amelioration of behavioral deficits, there is only limited information on its potential effects on neurodegeneration. In the current study, we assessed whether long-term caffeine consumption affects hippocampal neuron loss and associated behavioral deficits in the Tg4-42 mouse model of AD. Treatment over a 4 months period reduced hippocampal neuron loss, rescued learning and memory deficits and ameliorates impaired neurogenesis. Neuron-specific hippocampal transcriptome analysis revealed an altered expression profile with an up-regulation of genes linked to synaptic function and processes, as well as neural progenitor proliferation. Treatment of 5xFAD mice with the same paradigm also rescued behavioral deficits, however, without affecting extracellular amyloid-beta (Abeta) levels or altered APP processing.

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Neurodegeneration. C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits.

Project description:The major genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis is a G4C2 repeat expansion in C9ORF72. Efforts to combat neurodegeneration associated with "c9FTD/ALS" are hindered by a lack of animal models recapitulating disease features. We developed a mouse model to mimic both neuropathological and clinical c9FTD/ALS phenotypes. We expressed (G4C2)66 throughout the murine central nervous system by means of somatic brain transgenesis mediated by adeno-associated virus. Brains of 6-month-old mice contained nuclear RNA foci, inclusions of poly(Gly-Pro), poly(Gly-Ala), and poly(Gly-Arg) dipeptide repeat proteins, as well as TDP-43 pathology. These mouse brains also exhibited cortical neuron and cerebellar Purkinje cell loss, astrogliosis, and decreased weight. (G4C2)66 mice also developed behavioral abnormalities similar to clinical symptoms of c9FTD/ALS patients, including hyperactivity, anxiety, antisocial behavior, and motor deficits.

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