Computational analysis of transcriptome signature repurposes low dose trifluoperazine for the treatment of fragile X syndrome in mouse model

ABSTRACTFragile X syndrome (FXS), caused by mutations in fragile X mental retardation 1 gene (FMR1), is a prevailing genetic disorder of intellectual disability and autism. Currently, there is no efficacious medication for FXS. Here, we use transcriptome landscape as a holistic molecular phenotype/endpoint to identify potential therapeutic intervention. Through in silico screening with public gene signature database, computational analysis of transcriptome profile in Fmr1 knockout (KO) neurons predicts therapeutic value of an FDA-approved drug trifluoperazine. Through experimental validation, we find that systemic administration of low dose trifluoperazine at 0.05 mg/kg attenuates multiple FXS- and autism-related behavioral symptoms. Moreover, computational analysis of transcriptome alteration caused by trifluoperazine suggests a new mechanism of action against PI3K (Phosphatidylinositol-4,5-bisphosphate 3-kinase) activity. Consistently, trifluoperazine suppresses PI3K activity and its down-stream targets Akt (protein kinase B) and S6K1 (S6 kinase 1) in neurons. Further, trifluoperazine normalizes the aberrantly elevated activity of Akt and S6K1 and enhanced protein synthesis in FXS mouse. In conclusion, our data demonstrate promising value of gene signature-based computation in identification of therapeutic strategy and repurposing drugs for neurological disorders, and suggest trifluoperazine as a potential practical treatment for FXS.

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A Randomized, Double-Blind, Placebo-Controlled Trial of Low-Dose Sertraline in Young Children With Fragile X Syndrome

Journal of Developmental & Behavioral Pediatrics ◽

10.1097/dbp.0000000000000334 ◽

2016 ◽

Vol 37 (8) ◽

pp. 619-628 ◽

Cited By ~ 37

Author(s):

Laura Greiss Hess ◽

Sarah E. Fitzpatrick ◽

Danh V. Nguyen ◽

Yanjun Chen ◽

Kimberly N. Gaul ◽

...

Keyword(s):

Young Children ◽

Fragile X Syndrome ◽

Low Dose ◽

Fragile X ◽

Controlled Trial ◽

Double Blind ◽

Double Blind Placebo

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Fragile X Syndrome: A Genetic Disorder to Consider in Patients with Speech Delay

Turkish Journal of Pediatric Disease ◽

10.12956/tjpd.2018.359 ◽

2018 ◽

Author(s):

Tuba ÇELEN YOLDAŞ ◽

Gülen Eda UTİNE ◽

Elif Nursel ÖZMERT ◽

Koray BODUROĞLU

Keyword(s):

Fragile X Syndrome ◽

Fragile X ◽

Genetic Disorder ◽

Speech Delay

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Family as a Context for Child Development: Mothers with the FMR1 Premutation and Their Children with Fragile X Syndrome

Seminars in Speech and Language ◽

10.1055/s-0041-1730988 ◽

2021 ◽

Vol 42 (04) ◽

pp. 277-286

Author(s):

Katherine Bangert ◽

Carly Moser ◽

Laura Friedman ◽

Jessica Klusek

Keyword(s):

Fragile X Syndrome ◽

Family Environment ◽

Fragile X ◽

Genetic Disorder ◽

Challenging Behaviors ◽

Fmr1 Gene ◽

Fmr1 Premutation ◽

Children And Parents ◽

Increased Risk ◽

Outcomes For Children

AbstractFragile X syndrome (FXS) is a genetic disorder caused by changes of the FMR1 gene that is passed along among families. A range of developmental processes may be impacted with wide variation in abilities across individuals with FXS. Mothers of children with FXS are often carriers of a “premutation” expansion on the FMR1 gene, which is associated with its own clinical phenotype. These maternal features may increase individual and family vulnerabilities, including increased risk for depression and anxiety disorders and difficulties in social and cognitive ability. These characteristics may worsen with age, and potentially interact with a child's challenging behaviors and with family dynamics. Thus, families of children with FXS may experience unique challenges related to genetic risk, manifested across both children and parents, that should be considered in therapeutic planning to optimize outcomes for children and their families. In this article, we review core features of the FMR1 premutation as expressed in mothers and aspects of the family environment that interface with developmental outcomes of children with FXS. Recommendations for family-centered support services are discussed.

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Carbamazepine Restores Neuronal Signaling, Protein Synthesis, and Cognitive Function in a Mouse Model of Fragile X Syndrome

International Journal of Molecular Sciences ◽

10.3390/ijms21239327 ◽

2020 ◽

Vol 21 (23) ◽

pp. 9327

Author(s):

Qi Ding ◽

Fan Zhang ◽

Yue Feng ◽

Hongbing Wang

Keyword(s):

Protein Synthesis ◽

Fragile X Syndrome ◽

Fragile X ◽

Genetic Disorder ◽

Cellular Level ◽

Neuronal Signaling ◽

Object Location Memory ◽

Extracellular Signal ◽

Elevated Protein ◽

Phosphoinositide 3 Kinase

Fragile X syndrome (FXS) is a leading genetic disorder of intellectual disability caused by the loss of the functional fragile X mental retardation protein (FMRP). To date, there is no efficacious mechanism-based medication for FXS. With regard to potential disease mechanisms in FXS, it is widely accepted that the lack of FMRP causes elevated protein synthesis and deregulation of neuronal signaling. Abnormal enhancement of the ERK½ (extracellular signal-regulated kinase ½) and PI3K-Akt (Phosphoinositide 3 kinase-protein kinase B) signaling pathways has been identified in both FXS patients and FXS mouse models. In this study, we show that carbamazepine, which is an FDA-approved drug and has been mainly used to treat seizure and neuropathic pain, corrects cognitive deficits including passive avoidance and object location memory in FXS mice. Carbamazepine also rescues hyper locomotion and social deficits. At the cellular level, carbamazepine dampens the elevated level of ERK½ and Akt signaling as well as protein synthesis in FXS mouse neurons. Together, these results advocate repurposing carbamazepine for FXS treatment.

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Carbamazepine restores neuronal signaling, protein synthesis and cognitive function in a mouse model of fragile X syndrome

10.1101/2020.01.07.897835 ◽

2020 ◽

Author(s):

Qi Ding ◽

Fan Zhang ◽

Yue Feng ◽

Hongbing Wang

Keyword(s):

Protein Synthesis ◽

Fragile X Syndrome ◽

Fragile X ◽

Genetic Disorder ◽

Cellular Level ◽

Neuronal Signaling ◽

Object Location Memory ◽

Extracellular Signal ◽

Elevated Protein ◽

Phosphoinositide 3 Kinase

ABSTRACTFragile X syndrome (FXS) is a leading genetic disorder of intellectual disability caused by the loss of the functional fragile X mental retardation protein (FMRP). To date, there is no efficacious mechanism-based medication for FXS. With regard to potential disease mechanisms in FXS, it is widely accepted that the lack of FMRP causes elevated protein synthesis and deregulation of neuronal signaling. Abnormal enhancement of the ERK½ (extracellular signal-regulated kinase ½) and PI3K-Akt (Phosphoinositide 3 kinase-protein kinase B) signaling pathways has been identified in both FXS patients and FXS mouse models. In this study, we show that carbamazepine, which is an FDA-approved drug and has been mainly used to treat seizure and neuropathic pain, corrects cognitive deficits including passive avoidance and object location memory in FXS mice. Carbamazepine also rescues hyper locomotion and social deficits. At the cellular level, carbamazepine dampens the elevated level of ERK½ and Akt signaling as well as protein synthesis in FXS mouse neurons. Together, these results advocate repurposing carbamazepine for FXS treatment.

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Mitochondrial bioenergetics of astrocytes in Fragile X Syndrome: new perspectives from culture conditions and sex effects

AJP Cell Physiology ◽

10.1152/ajpcell.00130.2021 ◽

2021 ◽

Author(s):

Gregory G. Vandenberg ◽

Aasritha Thotakura ◽

Angela L. Scott

Keyword(s):

Oxidative Stress ◽

Reactive Oxygen Species ◽

Fragile X Syndrome ◽

Fragile X ◽

Genetic Disorder ◽

Reactive Oxygen ◽

Oxygen Availability ◽

Mitochondrial Bioenergetics ◽

Oxygen Species

Fragile X syndrome is a genetic disorder that is characterized by a range of cognitive and behavioural deficits, including mild-moderate intellectual disability. The disease is characterized by an X-linked mutation of the Fmr1 gene, which causes silencing of the gene coding for FMRP, a translational regulator integral for neurodevelopment. Mitochondrial dysfunction has been recently associated with FXS, with reports of increases in oxidative stress markers, reactive oxygen species, and lipid peroxidation being present in brain tissue. Astrocytes, a prominent glial cell within the CNS, plays a large role in regulating oxidative homeostasis within the developing brain and dysregulation of astrocyte redox balance in FXS may contribute to oxidative stress. Astrocyte function and mitochondrial bioenergetics is significantly influenced by oxygen availability as well as circulating sex hormones; yet these parameters are rarely considered during in vitro experimentation. Given that the brain normally develops in a range of hypoxic conditions and FXS is a sex-linked genetic disorder, we investigated how different oxygen levels (normoxic versus hypoxic) and biological sex affected mitochondrial bioenergetics of astrocytes in FXS. Our results show demonstrate that both mitochondrial respiration capacity and reactive oxygen species emission are altered with Fmr1 deletion in astrocytes and these changes were dependent upon both sexual dimorphism and oxygen availability.

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EEG Signal Complexity Is Reduced During Resting-State in Fragile X Syndrome

Frontiers in Psychiatry ◽

10.3389/fpsyt.2021.716707 ◽

2021 ◽

Vol 12 ◽

Author(s):

Mélodie Proteau-Lemieux ◽

Inga Sophia Knoth ◽

Kristian Agbogba ◽

Valérie Côté ◽

Hazel Maridith Barlahan Biag ◽

...

Keyword(s):

Fragile X Syndrome ◽

Resting State ◽

Fragile X ◽

Genetic Disorder ◽

Age Distribution ◽

Replication Study ◽

Brain Maturation ◽

Alpha Power ◽

Cortical Hyperexcitability ◽

Signal Complexity

Introduction: Fragile X syndrome (FXS) is a genetic disorder caused by a mutation of the fragile X mental retardation 1 gene (FMR1). FXS is associated with neurophysiological abnormalities, including cortical hyperexcitability. Alterations in electroencephalogram (EEG) resting-state power spectral density (PSD) are well-defined in FXS and were found to be linked to neurodevelopmental delays. Whether non-linear dynamics of the brain signal are also altered remains to be studied.Methods: In this study, resting-state EEG power, including alpha peak frequency (APF) and theta/beta ratio (TBR), as well as signal complexity using multi-scale entropy (MSE) were compared between 26 FXS participants (ages 5–28 years), and 7 neurotypical (NT) controls with a similar age distribution. Subsequently a replication study was carried out, comparing our cohort to 19 FXS participants independently recorded at a different site.Results: PSD results confirmed the increased gamma, decreased alpha power and APF in FXS participants compared to NT controls. No alterations in TBR were found. Importantly, results revealed reduced signal complexity in FXS participants, specifically in higher scales, suggesting that altered signal complexity is sensitive to brain alterations in this population. The replication study mostly confirmed these results and suggested critical points of stagnation in the neurodevelopmental curve of FXS.Conclusion: Signal complexity is a powerful feature that can be added to the electrophysiological biomarkers of brain maturation in FXS.

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