Fluoxetine ameliorates mucopolysaccharidosis type IIIA

Capuozzo, Antonella; Montefusco, Sandro; Cacace, Vincenzo; Miceli, Sofia; Esposito, Alessandra; Napolitano, Gennaro; Eduardo, Nusco; Polishchuk, Elena; Teresa, Pizzo Maria; Maria, De Risi; Elvira, De Leonibus; Cristina, Sorrentino Nicolina; Luis, Medina Diego

doi:10.1016/j.ymthe.2022.01.037

Cited by 17 publications

(15 citation statements)

References 55 publications

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“…Nevertheless, TFEB is a non-canonical substrate of mTOR and can be activated by inhibitors that impact Rags pathways but not on canonical mTOR substrate, such as the ribosomal protein S6 kinase (S6K). For example, in a recently published paper, the mTOR inhibitor fluoxetine was identified as a possible corrector of neurodegeneration in MPS-IIIA via TFEB activation in a Rag-dependent manner [ 153 ]. This suggests that careful evaluation of mTOR inhibitors should be performed before moving them towards tests in pre-clinical models for neurodegenerative diseases or to clinical trials.…”

Section: Mitf/tfe Family Transcription Factors: Putative Therapeutic ...mentioning

confidence: 99%

The Regulation of MiTF/TFE Transcription Factors Across Model Organisms: from Brain Physiology to Implication for Neurodegeneration

et al. 2022

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The microphthalmia/transcription factor E (MiTF/TFE) transcription factors are responsible for the regulation of various key processes for the maintenance of brain function, including autophagy-lysosomal pathway, lipid catabolism, and mitochondrial homeostasis. Among them, autophagy is one of the most relevant pathways in this frame; it is evolutionary conserved and crucial for cellular homeostasis. The dysregulation of MiTF/TFE proteins was shown to be involved in the development and progression of neurodegenerative diseases. Thus, the characterization of their function is key in the understanding of the etiology of these diseases, with the potential to develop novel therapeutics targeted to MiTF/TFE proteins and to the autophagic process. The fact that these proteins are evolutionary conserved suggests that their function and dysfunction can be investigated in model organisms with a simpler nervous system than the mammalian one. Building not only on studies in mammalian models but also in complementary model organisms, in this review we discuss (1) the mechanistic regulation of MiTF/TFE transcription factors; (2) their roles in different regions of the central nervous system, in different cell types, and their involvement in the development of neurodegenerative diseases, including lysosomal storage disorders; (3) the overlap and the compensation that occur among the different members of the family; (4) the importance of the evolutionary conservation of these protein and the process they regulate, which allows their study in different model organisms; and (5) their possible role as therapeutic targets in neurodegeneration.

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Section: Mitf/tfe Family Transcription Factors: Putative Therapeutic ...mentioning

confidence: 99%

The Regulation of MiTF/TFE Transcription Factors Across Model Organisms: from Brain Physiology to Implication for Neurodegeneration

et al. 2022

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“…The significance level was set at p < 0.05 for all the experiments; data are expressed as mean ± standard errors (SEM). The number of mice per group was calculated a priori with power analysis using G * Power 3.1 software [63][64][65] with α = 0.05 and power (1 − β) = 0.80, and data were inspected for normal distribution through a Shapiro-Wilk test. Significant outliers were calculated at the alpha level 0.05, through the online free software Outlier Calculator by GraphPad (available at https://www.graphpad.com/quickcalcs/Grubbs1.cfm), which employs Grubbs' test to define a significant outlier.…”

Section: Statisticsmentioning

confidence: 99%

Section: Statisticsmentioning

confidence: 99%

Thalamo-hippocampal pathway regulates incidental memory load in mice

Torromino

Loffredo

Cavezza

et al. 2021

Preprint

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Memory can be challenged by increasing both its required duration and the amount of information to be encoded, namely the memory load. The dorsal hippocampus (dHP) has been involved in memory consolidation, which is the stabilization of a trace from short-term (STM) to long-term memory (LTM), as well as in the ability to process high information load. However, how memory load influences memory consolidation, and the underlying neural mechanisms, are yet unknown. To address this question, we used male and female mice that, despite having in our Different Object recognition Task (DOT) the same STM capacity of 6 objects, spontaneously show differences in the number of objects directly transferred to LTM, when tested over longer delays. Males memorize all 6 objects encoded, while females remember only up to 4, both at 1 and 24 h delays. Interestingly, males activate more the dHP (as measured by c-Fos expression), while females the thalamic nucleus reuniens (RE). Optogenetic inhibition of the RE-dHP pathway during off-line memory consolidation favors 6-object LTM retention in females by removing inhibitory control over dHP activation, while chemogenetic RE-activation impairs it in males. Our data represent a first demonstration of a sub-cortical control of dHP recruitment, that might underlie its sex-dependent activation during incidental memory, with potential also for clinical application.

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“…Retinal degeneration in MPS-IIIA mice is accompanied by heparan sulfate accumulation, defective autophagy flux and reactive microgliosis ( Intartaglia et al, 2020 ). A recent study reports a promising therapy of MPSIIIa using fluoxetine, a serotonin reuptake inhibitor that also activates TFEB, a transcriptional activator of lysosomal and autophagy functions ( Capuozzo et al, 2022 ). In vivo treatment of MPS-IIIA mice with fluoxetine decreases glycosaminoglycan accumulation and aggregated autophagy substrates.…”

Section: Introductionmentioning

confidence: 99%

Regulation of autophagy, lipid metabolism, and neurodegenerative pathology by heparan sulfate proteoglycans

Schultheis

Becker²,

Berhanu³

et al. 2023

Front. Genet.

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Heparan sulfate modified proteins or proteoglycans (HSPGs) are an abundant class of cell surface and extracellular matrix molecules. They serve important co-receptor functions in the regulation of signaling as well as membrane trafficking. Many of these activities directly affect processes associated with neurodegeneration including uptake and export of Tau protein, disposition of Amyloid Precursor Protein-derived peptides, and regulation of autophagy. In this review we focus on the impact of HSPGs on autophagy, membrane trafficking, mitochondrial quality control and biogenesis, and lipid metabolism. Disruption of these processes are a hallmark of Alzheimer’s disease (AD) and there is evidence that altering heparan sulfate structure and function could counter AD-associated pathological processes. Compromising presenilin function in several systems has provided instructive models for understanding the molecular and cellular underpinnings of AD. Disrupting presenilin function produces a constellation of cellular deficits including accumulation of lipid, disruption of autophagosome to lysosome traffic and reduction in mitochondrial size and number. Inhibition of heparan sulfate biosynthesis has opposing effects on all these cellular phenotypes, increasing mitochondrial size, stimulating autophagy flux to lysosomes, and reducing the level of intracellular lipid. These findings suggest a potential mechanism for countering pathology found in AD and related disorders by altering heparan sulfate structure and influencing cellular processes disrupted broadly in neurodegenerative disease. Vertebrate and invertebrate model systems, where the cellular machinery of autophagy and lipid metabolism are conserved, continue to provide important translational guideposts for designing interventions that address the root cause of neurodegenerative pathology.

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Fluoxetine ameliorates mucopolysaccharidosis type IIIA

Cited by 17 publications

References 55 publications

The Regulation of MiTF/TFE Transcription Factors Across Model Organisms: from Brain Physiology to Implication for Neurodegeneration

The Regulation of MiTF/TFE Transcription Factors Across Model Organisms: from Brain Physiology to Implication for Neurodegeneration

Thalamo-hippocampal pathway regulates incidental memory load in mice

Regulation of autophagy, lipid metabolism, and neurodegenerative pathology by heparan sulfate proteoglycans

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