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Insulin resistance disrupts midbrain metabolic and functional homeostasis and aggravates dopaminergic neuron loss in GBA-PD via FOXO1 overexpression [WTvsGBA]

ABSTRACT: Insulin resistance disrupts midbrain metabolic and functional homeostasis and aggravates dopaminergic neuron loss in GBA-PD via FOXO1 overexpression [WTvsGBA]

PROVIDER: PRJNA993989 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25243540_1.fastq.gz	Fastqsanger.gz
	SRR25243540_2.fastq.gz	Fastqsanger.gz
	SRR25243541_1.fastq.gz	Fastqsanger.gz
	SRR25243541_2.fastq.gz	Fastqsanger.gz
	SRR25243542_1.fastq.gz	Fastqsanger.gz

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Insulin resistance disrupts midbrain metabolic and functional homeostasis and aggravates dopaminergic neuron loss in GBA-PD via FOXO1 overexpression [WTvsGBA]

Project description:Growing evidence indicates that Type 2 diabetes (T2D) is associated with an increased risk of developing PD Parkinson’s disease (PD) through shared disease mechanisms. Studies show that insulin resistance, which is the driving pathophysiological mechanism of T2D plays a major role in neurodegeneration by impairing neuronal functionality, metabolism, and survival. To better understand the importance of insulin signalling in the human midbrain, which is the most affected brain region in PD, we expose IPSC-derived human midbrain organoids from healthy individuals and GBA-N370S mutation-carrying PD patients to either high insulin concentrations, promoting insulin resistance, or to more physiological insulin concentrations restoring normal insulin signalling function. We are able to show that insulin resistance compromises dopaminergic neuron and dopamine levels in the midbrain organoids of healthy donors. Moreover, insulin-resistant organoids display diminished neuronal activity and reduced metabolic efficiency. Furthermore, our findings demonstrate FOXO1 role in GBA-PD phenotype severity and show the potential beneficial effects of the anti-diabetic drug Pioglitazone in GBA-PD treatment. Overall, our results highlight insulin resistance as a significant target in PD prevention and disease-modifying therapy.

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Insulin resistance disrupts midbrain metabolic and functional homeostasis and aggravates dopaminergic neuron loss in GBA-PD via FOXO1 overexpression [WTs]

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Insulin resistance disrupts midbrain metabolic and functional homeostasis and aggravates dopaminergic neuron loss in GBA-PD via FOXO1 overexpression.

Project description:Insulin resistance disrupts midbrain metabolic and functional homeostasis and aggravates dopaminergic neuron loss in GBA-PD via FOXO1 overexpression.

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Insulin resistance disrupts midbrain metabolic and functional homeostasis and aggravates dopaminergic neuron loss in GBA-PD via FOXO1 overexpression [WTs]

Project description:Insulin resistance disrupts midbrain metabolic and functional homeostasis and aggravates dopaminergic neuron loss in GBA-PD via FOXO1 overexpression [WTs]

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Cell cycle arrest of neural progenitors causes impaired dopaminergic neuronal differentiation in GBA associated Parkinson’s disease midbrain organoids [2]

Project description:The mechanisms underlying Parkinson's disease (PD) etiology are only partially understood despite intensive research conducted in the field. Recent evidence suggests that early neurodevelopmental defects might play a role in cellular susceptibility to neurodegeneration. To study the early developmental contribution of GBA mutations in PD we used patient-derived iPSCs carrying a heterozygous N370S mutation in the GBA gene. Patient-specific midbrain organoids displayed GBA-PD relevant phenotypes such as reduction of GCase activity, autophagy impairment and mitochondrial dysfunction. Genome-scale metabolic (GEM) modeling predicted changes in lipid metabolism which were validated with lipidomics analysis, showing significant differences in the lipidome of GBA-PD. In addition, patient-specific midbrain organoids exhibited an increase in the neural progenitor population showing signs of cellular senescence. This was accompanied by a decrease in the number and complexity of dopaminergic neurons. These results provide insights into how GBA mutations may lead to neurodevelopmental defects thereby predisposing to PD pathology.

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Cell cycle arrest of neural progenitors causes impaired dopaminergic neuronal differentiation in GBA associated Parkinson’s disease midbrain organoids [1]

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