The Role of Lysophosphatidic Acid in Neuropsychiatric and Neurodegenerative Disorders

Dedoni, Simona; Camoglio, Chiara; Siddi, Carlotta; Scherma, Maria; Fratta, Walter; Fadda, Paola

doi:10.3390/futurepharmacol4010014

Cited by 2 publications

(1 citation statement)

References 149 publications

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“…Pyk2 has also been implicated in neurodegenerative diseases such as Alzheimer’s and Huntington’s disease ( Lambert et al, 2013 ; Giralt et al, 2018 ; Kilinc et al, 2020 ). In neurons, Pyk2 has been shown to activate Gsk3β ( Theos et al, 2005 ; Dedoni et al, 2024 ).…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial translation failure represses cholesterol gene expression via Pyk2-Gsk3β-Srebp2 axis

Toshima,

Yagi,

et al. 2024

Life Sci. Alliance

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Neurodegenerative diseases and other age-related disorders are closely associated with mitochondrial dysfunction. We previously showed that mice with neuron-specific deficiency of mitochondrial translation exhibit leukoencephalopathy because of demyelination. Reduced cholesterol metabolism has been associated with demyelinating diseases of the brain such as Alzheimer’s disease. However, the molecular mechanisms involved and relevance to the pathogenesis remained unknown. In this study, we show that inhibition of mitochondrial translation significantly reduced expression of the cholesterol synthase genes and degraded their sterol-regulated transcription factor, sterol regulatory element-binding protein 2 (Srebp2). Furthermore, the phosphorylation of Pyk2 and Gsk3β was increased in the white matter of p32cKO mice. We observed that Pyk2 inhibitors reduced the phosphorylation of Gsk3β and that GSK3β inhibitors suppressed degradation of the transcription factor Srebp2. The Pyk2–Gsk3β axis is involved in the ubiquitination of Srebp2 and reduced expression of cholesterol gene. These results suggest that inhibition of mitochondrial translation may be a causative mechanism of neurodegenerative diseases of aging. Improving the mitochondrial translation or effectiveness of Gsk3β inhibitors is a potential therapeutic strategy for leukoencephalopathy.

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Section: Introductionmentioning

confidence: 99%

Mitochondrial translation failure represses cholesterol gene expression via Pyk2-Gsk3β-Srebp2 axis

Toshima,

Yagi,

et al. 2024

Life Sci. Alliance

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N88S seipin-related seipinopathy is a lipidopathy associated with loss of iron homeostasis

Ribeiro,

Oliveira,

Nogueira

et al. 2024

Preprint

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Background Seipin is a protein encoded by the BSCL2 gene in humans and SEI1 gene in yeast, forming an Endoplasmic Reticulum (ER)-bound homo-oligomer. This oligomer is crucial in targeting ER-lipid droplet (LD) contact sites, facilitating the delivery of triacylglycerol (TG) to nascent LDs. Mutations in BSCL2, particularly N88S and S90L, lead to seipinopathies, which correspond to a cohort of motor neuron diseases (MNDs) characterized by the accumulation of misfolded N88S seipin into inclusion bodies (IBs) and cellular dysfunctions. Methods Quantitative untargeted mass spectrometric proteomic and lipidomic analyses were conducted to examine changes in protein and lipid abundance in wild-type (WT) versus N88S seipin-expressing mutant cells. Differentially expressed proteins were categorized into functional networks to highlight altered protein functions and signaling pathways. Statistical comparisons were made using unpaired, two-tailed Student's t-tests or two-way ANOVA. P-values < 0.05 are considered significant. Results In a well-established yeast model of N88S seipinopathy, misfolded N88S seipin forms IBs and exhibits higher levels of ER stress, leading to decreased cell viability due to increased reactive oxygen species (ROS), oxidative damage, lipid peroxidation, and reduced antioxidant activity. Proteomic and lipidomic analyses revealed alterations in phosphatidic acid (PA) levels, associated with disrupted inositol metabolism and decreased flux towards phospholipid biosynthesis. Importantly, deregulation of lipid metabolism contributed to ER stress beyond N88S seipin misfolding and IB formation. Additionally, the model exhibited deregulated iron (Fe) homeostasis during lifespan. N88S seipin-expressing cells showed impaired ability to cope with iron deficiency. This was linked to changes in the expression of Aft1p-controlled iron regulon genes, including the mRNA-binding protein CTH2 and the high-affinity iron transport system member FET3, in a p38/Hog1p- and Msn2p/Msn4p-dependent manner. Importantly, we unraveled a novel link between inositol metabolism and activation of the iron regulon in cells expressing the N88S seipin mutation. Despite iron accumulation, this was not associated with oxidative stress. Conclusions The study highlights that the effects of N88S seipin mutation extend beyond protein misfolding, with significant disruptions in lipid metabolism and iron homeostasis. This research marks a significant advance in understanding and defining the roles of proteins and signaling pathways that contribute to human seipinopathy. Altered cellular processes, as well as potential therapeutic targets and biomarkers, were identified and can be explored in translational studies using human cell models.

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The Role of Lysophosphatidic Acid in Neuropsychiatric and Neurodegenerative Disorders

Cited by 2 publications

References 149 publications

Mitochondrial translation failure represses cholesterol gene expression via Pyk2-Gsk3β-Srebp2 axis

Mitochondrial translation failure represses cholesterol gene expression via Pyk2-Gsk3β-Srebp2 axis

N88S seipin-related seipinopathy is a lipidopathy associated with loss of iron homeostasis

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