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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE237116 | GEO | 2024/10/01

REPOSITORIES: GEO

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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.

2024-10-01 | GSE237115 | GEO

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

2024-10-01 | GSE237114 | GEO

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

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

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Myeloid FBW7 deficiency disrupts redox homeostasis and aggravates dietary-induced insulin resistance.

Project description:The E3 ubiquitin ligase FBW7 plays critical roles in multiple pathological and physiological processes. Here, we report that after high-fat diet (HFD) feeding for 16 weeks, myeloid-specific FBW7-deficient mice demonstrate increased redox stress, inflammatory responses and insulin resistance. Macrophages activation under FBW7 deficiency decreases substrate flux through the pentose phosphate pathway (PPP) to produce less equivalents (NADPH and GSH) and aggravate the generation of intracellular reactive oxygen species (ROS) in macrophages, thereby over-activating proinflammatory reaction. Mechanistically, we identify that pyruvate kinase muscle isozyme M2 (PKM2) is a new bona fide ubiquitin substrate of SCFFBW7. While challenged with HFD stress, pharmacological inhibition of PKM2 protects FBW7-deficient macrophages against production of ROS, proinflammatory reaction and insulin resistance. Intriguingly, we further find an inverse correlation between FBW7 level and relative higher H2O2 level and the severity of obesity-related diabetes. Overall, the results suggest that FBW7 can play a crucial role in modulating inflammatory response through maintaining the intracellular redox homeostasis during HFD insults.

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