<i>Pten</i>
            heterozygosity restores neuronal morphology in fragile X syndrome mice

Sathyanarayana, Shivaprasad H.; Saunders, Jasmine A; Slaughter, Jacob; Tariq, Kamran; Chakrabarti, Rajarshi; Sadanandappa, Madhumala K.; Luikart, Bryan W.; Bosco, Giovanni

doi:10.1073/pnas.2109448119

Cited by 9 publications

(4 citation statements)

References 65 publications

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“…Increasing evidence links PTEN to neurodevelopmental and neurodegenerative diseases [44,45]. PTEN translation is negatively regulated by FMRP and heterozygous loss of Pten rescued neuronal phenotypes in an Fmr1 knockout mouse [55]. Moreover, it has been shown that PTEN knockdown or pharmacological inhibition is beneficial for MN survival and neuromuscular innervation in non-FUS ALS and spinal muscular atrophy models [46][47][48]56].…”

Section: Discussionmentioning

confidence: 99%

Digital color-coded molecular barcoding reveals dysregulation of common FUS and FMRP targets in soma and neurites of ALS mutant motoneurons

2023

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Mutations in RNA binding proteins (RBPs) have been linked to the motor neuron disease amyotrophic lateral sclerosis (ALS). Extensive auto-regulation, cross-regulation, cooperation and competition mechanisms among RBPs are in place to ensure proper expression levels of common targets, often including other RBPs and their own transcripts. Moreover, several RBPs play a crucial role in the nervous system by localizing target RNAs in specific neuronal compartments. These include the RBPs FUS, FMRP, and HuD. ALS mutations in a given RBP are predicted to produce a broad impact on such delicate equilibrium. Here we studied the effects of the severe FUS-P525L mutation on common FUS and FMRP targets. Expression profiling by digital color-coded molecular barcoding in cell bodies and neurites of human iPSC-derived motor neurons revealed altered levels of transcripts involved in the cytoskeleton, neural projection and synapses. One of the common targets is HuD, which is upregulated because of the loss of FMRP binding to its 3′UTR due to mutant FUS competition. Notably, many genes are commonly altered upon FUS mutation or HuD overexpression, suggesting that a substantial part of the effects of mutant FUS on the motor neuron transcriptome could be due to HuD gain-of-function. Among altered transcripts, we also identified other common FUS and FMRP targets, namely MAP1B, PTEN, and AP2B1, that are upregulated upon loss of FMRP binding on their 3’UTR in FUS-P525L motor neurons. This work demonstrates that the impairment of FMRP function by mutant FUS might alter the expression of several genes, including new possible biomarkers and therapeutic targets for ALS.

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Section: Discussionmentioning

confidence: 99%

Digital color-coded molecular barcoding reveals dysregulation of common FUS and FMRP targets in soma and neurites of ALS mutant motoneurons

2023

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“…PTEN is a master inhibitor of cell growth, survival, and differentiation (Tariq et al, 2022). Overexpression of PTEN leads to reduced neuronal growth, axon growth, and dendritic branching (Sathyanarayana et al, 2022). Moreover, inhibition of PTEN following middle cerebral artery occlusion (MCAO) improved neuronal survival, dendritic arborization, and motor deficits (Mao et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Impaired cortical neuronal homeostasis and cognition after diffuse traumatic brain injury are dependent on microglia and type I interferon responses

Packer,

Bray,

Beckman

et al. 2023

Glia

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Neuropsychiatric complications including depression and cognitive decline develop in the years after traumatic brain injury (TBI), negatively affecting quality of life. Microglial and type 1 interferon (IFN‐I) responses are associated with the transition from acute to chronic neuroinflammation after diffuse TBI in mice. Thus, the purpose of this study was to determine if impaired neuronal homeostasis and increased IFN‐I responses intersected after TBI to cause cognitive impairment. Here, the RNA profile of neurons and microglia after TBI (single nucleus RNA‐sequencing) with or without microglia depletion (CSF1R antagonist) was assessed 7 dpi. There was a TBI‐dependent suppression of cortical neuronal homeostasis with reductions in CREB signaling, synaptogenesis, and synaptic migration and increases in RhoGDI and PTEN signaling (Ingenuity Pathway Analysis). Microglial depletion reversed 50% of TBI‐induced gene changes in cortical neurons depending on subtype. Moreover, the microglial RNA signature 7 dpi was associated with increased stimulator of interferon genes (STING) activation and IFN‐I responses. Therefore, we sought to reduce IFN‐I signaling after TBI using STING knockout mice and a STING antagonist, chloroquine (CQ). TBI‐associated cognitive deficits in novel object location and recognition (NOL/NOR) tasks at 7 and 30 dpi were STING dependent. In addition, TBI‐induced STING expression, microglial morphological restructuring, inflammatory (Tnf, Cd68, Ccl2) and IFN‐related (Irf3, Irf7, Ifi27) gene expression in the cortex were attenuated in STINGKO mice. CQ also reversed TBI‐induced cognitive deficits and reduced TBI‐induced inflammatory (Tnf, Cd68, Ccl2) and IFN (Irf7, Sting) cortical gene expression. Collectively, reducing IFN‐I signaling after TBI with STING‐dependent interventions attenuated the prolonged microglial activation and cognitive impairment.

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“…The PTEN protein is part of a signaling network that contains multiple autism spectrum disorder (ASD)-associated gene products and represents a potentially common etiological mechanism for ASD and related neurodevelopmental disorders (Rademacher et al, 2019;Cummings et al, 2022). PTEN translation is negatively regulated by FMRP and heterozygous loss of Pten rescued neuronal phenotypes in a Fmr1 knockout mouse (Sathyanarayana et al, 2022). Moreover, it has been shown that PTEN knockdown by RNA interference is beneficial for MN survival in SOD1-and C9ORF72-ALS and spinal muscular atrophy models (Kirby et al, 2011;Little et al, 2015;Stopford et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Digital color-coded molecular barcoding reveals dysregulation of common FUS and FMRP targets in soma and neurites of ALS mutant motoneurons

Garone

Salerno

Rosa

2022

Preprint

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Mutations in RNA binding proteins (RBPs) have been linked to the motor neuron disease amyotrophic lateral sclerosis (ALS). Extensive auto-regulation, cross-regulation, cooperation and competition mechanisms among RBPs are in place to ensure proper expression levels of common targets, often including other RBPs and their own transcripts. Moreover, several RBPs play a crucial role in the nervous system by localizing target RNAs in specific neuronal compartments. These include the RBPs FUS, FMRP and HuD. ALS mutations in a given RBP are predicted to produce a broad impact on such delicate equilibrium. Here we studied the effects of the severe FUS-P525L mutation on common FUS and FMRP targets. Expression profiling by digital color-coded molecular barcoding in cell bodies and neurites of human iPSC-derived motor neurons revealed altered levels of transcripts involved in cytoskeleton, neural projection and synapses. One of the common targets is HuD, which is upregulated because of the loss of FMRP binding to its 3’UTR due to mutant FUS competition. Notably, many genes are commonly altered upon FUS mutation or HuD overexpression, suggesting that a substantial part of the effects of mutant FUS on the motor neuron transcriptome could be due to HuD gain-of-function. Among altered transcripts we also identified other common FUS and FMRP targets, namely MAP1B, PTEN, and AP2B1, that are upregulated upon loss of FMRP binding on their 3’UTR in FUS-P525L motor neurons. This work demonstrates that the impairment of FMRP function by mutant FUS might alter the expression of several genes, including new possible biomarkers and therapeutic targets for ALS.

show abstract

Pten heterozygosity restores neuronal morphology in fragile X syndrome mice

Cited by 9 publications

References 65 publications

Digital color-coded molecular barcoding reveals dysregulation of common FUS and FMRP targets in soma and neurites of ALS mutant motoneurons

Digital color-coded molecular barcoding reveals dysregulation of common FUS and FMRP targets in soma and neurites of ALS mutant motoneurons

Impaired cortical neuronal homeostasis and cognition after diffuse traumatic brain injury are dependent on microglia and type I interferon responses

Digital color-coded molecular barcoding reveals dysregulation of common FUS and FMRP targets in soma and neurites of ALS mutant motoneurons

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