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A growing body of evidence implicates inflammation as a key hallmark in the pathophysiology of Parkinson’s disease (PD), with microglia playing a central role in mediating neuroinflammatory signaling in the brain. However, the molecular mechanisms linking microglial activation to dopaminergic neuron degeneration remain poorly understood. In this study, we investigated the contribution of the PD-associated LRRK2-G2019S mutation to microglial neurotoxicity using patient-derived induced pluripotent stem cell (iPSC) models. We found that LRRK2-G2019S mutant microglia exhibited elevated activation markers, enhanced phagocytic capacity, and increased secretion of pro-inflammatory cytokines such as TNF-α. These changes were associated with metabolic dysregulation, including upregulated glycolysis and impaired serine biosynthesis. In 3D midbrain organoids, these overactivated microglia resulted in dopaminergic neuron degeneration. Notably, treating LRRK2-G2019S microglia with oxamic acid, a glycolysis inhibitor, attenuated microglial inflammation and reduced neuronal loss. Our findings underscore the link between metabolic targeting in microglia and dopaminergic neuronal loss in LRRK2-G2019S mutation, and highlight a potential strategy that warrants further preclinical evaluation.

Amyotrophic lateral sclerosis (ALS) is a multifactorial motor neuron (MN) disease, characterized by several cellular dysfunctions, many of which are shared by different neurodegenerative diseases. Here, we investigated whether a stressful lifestyle might exacerbate the altered mechanisms and affect the disease progression in ALS-predisposed conditions. To model stress in vivo, SOD1G93A mice underwent a chronic unpredicted mild stress protocol. This resulted in a significant impairment in body weight gain and motor performance, in a gender-specific manner. Moreover, the gene expression of Col1a1, Col1a2 and Il6 was strongly dysregulated in motor cortex and/or spinal cord of stressed mice. To assess the direct impact of stress on MNs, NSC-34 hSOD1G93A cells underwent oxygen and glucose deprivation. Compared to NSC-34 hSOD1WT, mutated MNs exhibited a reduced capacity to cope with stress. By performing gene expression, protein-protein interaction, gene ontology and pathway enrichment analyses, we also revealed the pivotal role of the PI3K/Akt and focal adhesion pathways (triggered by Gsk3b, Il6, Igf1 and/or collagen) in mediating stress response. Similar results were observed in stressed human iPSCs-derived TARDBPG298S MNs. In conclusion, our results suggest that the PI3K/Akt and focal adhesion pathways play a crucial role in stress response across different ALS-predisposed models: the study paves the way for novel therapeutic targets and highlights the relevance of a healthy lifestyle.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-02167-9.

Mitochondrial function is modulated by its interaction with the endoplasmic reticulum (ER). Recent research indicates that these contacts are disrupted in familial models of amyotrophic lateral sclerosis (ALS). We report here that this impairment in the crosstalk between mitochondria and the ER impedes the use of glucose-derived pyruvate as mitochondrial fuel, causing a shift to fatty acids to sustain energy production. Over time, this deficiency alters mitochondrial electron flow and the active/dormant status of complex I in spinal cord tissues, but not in the brain. These findings suggest mitochondria-associated ER membranes (MAM domains) play a crucial role in regulating cellular glucose metabolism and that MAM dysfunction may underlie the bioenergetic deficits observed in ALS. The bioenergetic deficits observed in Amyotrophic Lateral Sclerosis result from the disruption of mitochondria-associated ER membranes. Here, the authors show that this disruption impairs the use of glucose-derived pyruvate, which over time hinders mitochondrial electron flow.