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

Mariana O. Ribeiro,

Mafalda Oliveira,

Verónica Nogueira

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 11, 2024

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

Language: Английский

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

Mariana O. Ribeiro,

Mafalda Oliveira,

Verónica Nogueira

et al.

Cell Communication and Signaling, Journal Year: 2025, Volume and Issue: 23(1)

Published: Jan. 7, 2025

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

Language: Английский

Citations

0
Role of Lysophosphatidic Acid in Neurological Diseases: From Pathophysiology to Therapeutic Implications DOI Creative Commons
Simona Dedoni, Valeria Avdoshina, Maria C. Olianas

et al.

Frontiers in Bioscience-Landmark, Journal Year: 2025, Volume and Issue: 30(5)

Published: April 30, 2025

Lysophosphatidic acid (LPA), a bioactive lipid molecule, has been identified as critical regulator of several cellular processes in the central nervous system, with significant impacts on neuronal function, synaptic plasticity, and neuroinflammatory responses. While Alzheimer’s disease, Multiple Sclerosis, Parkinson’s disease have garnered considerable attention due to their incidence socioeconomic significance, many additional neurological illnesses remain unclear terms underlying pathophysiology prospective treatment targets. This review synthesizes evidence linking LPA’s function diseases such traumatic brain injury, spinal cord cerebellar ataxia, cerebral ischemia, seizures, Huntington’s amyotrophic lateral sclerosis, Hutchinson-Gilford progeria syndrome, autism, migraine, human immunodeficiency virus (HIV)-associated complications Despite recent advances, specific mechanisms actions various disorders unknown, further research is needed understand distinct roles LPA across multiple conditions, well investigate therapeutic potential targeting receptors these pathologies. The purpose this highlight functions aforementioned diseases, which frequently share same poor prognosis scarcity truly effective therapies, while also evaluating role LPA, its receptors, signaling promising actors for development alternative strategies those proposed today.

Language: Английский

Citations

0
Mitochondrial translation failure represses cholesterol gene expression via Pyk2-Gsk3β-Srebp2 axis DOI Creative Commons

Takahiro Toshima,

Mikako Yagi,

Yura Do

et al.

Life Science Alliance, Journal Year: 2024, Volume and Issue: 7(7), P. e202302423 - e202302423

Published: May 8, 2024

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

Language: Английский

Citations

1
N88S seipin-related seipinopathy is a lipidopathy associated with loss of iron homeostasis DOI Creative Commons

Mariana O. Ribeiro,

Mafalda Oliveira,

Verónica Nogueira

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 11, 2024

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

Language: Английский

Citations

0