Alternative Splicing Modulates Protein Arginine Methyltransferase-Dependent Methylation of Fragile X Syndrome Mental Retardation Protein†

Biochemistry ◽  
2006 ◽  
Vol 45 (34) ◽  
pp. 10385-10393 ◽  
Author(s):  
Natalia Dolzhanskaya ◽  
George Merz ◽  
Robert B. Denman
Keyword(s):  
Mental Retardation ◽  
Alternative Splicing ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Protein Arginine Methyltransferase ◽  
Arginine Methyltransferase ◽  
Mental Retardation Protein

scholarly journals Role of microRNA Pathway in Mental Retardation

2007 ◽  
Vol 7 ◽  
pp. 146-154 ◽  
Author(s):  
Abrar Qurashi ◽  
Shuang Chang ◽  
Peng Jin
Keyword(s):  
Mental Retardation ◽  
Fragile X Syndrome ◽  
Genetic Basis ◽  
Fragile X ◽  
Biological Pathways ◽  
Fragile X Mental Retardation ◽  
Mental Retardation Protein ◽  
Mirna Pathway ◽  
Microrna Pathway

Deficits in cognitive functions lead to mental retardation (MR). Understanding the genetic basis of inherited MR has provided insights into the pathogenesis of MR. Fragile X syndrome is one of the most common forms of inherited MR, caused by the loss of functional Fragile X Mental Retardation Protein (FMRP).MicroRNAs (miRNAs) are endogenous, single-stranded RNAs between 18 and 25 nucleotides in length, which have been implicated in diversified biological pathways. Recent studies have linked the miRNA pathway to fragile X syndrome. Here we review the role of the miRNA pathway in fragile X syndrome and discuss its implication in MR in general.

scholarly journals The Fragile X Mental Retardation Protein: A Valuable Partner in the Battle against Epileptogenesis

2009 ◽  
Vol 9 (4) ◽  
pp. 116-118 ◽  
Author(s):  
Lisa R. Merlin
Keyword(s):  
Mental Retardation ◽  
Fragile X Syndrome ◽  
Metabotropic Glutamate Receptor ◽  
Mossy Fiber ◽  
Fragile X ◽  
Critical Role ◽  
Fmr1 Gene ◽  
Metabotropic Glutamate ◽  
Fragile X Mental Retardation ◽  
Mental Retardation Protein

Correction of Fragile X Syndrome in Mice. Dölen G, Osterweil E, Rao BSS, Smith GB, Auerbach BD, Chattarji S, Bear MF. Neuron 2007;56:955–962. Fragile X syndrome (FXS) is the most common form of heritable mental retardation and the leading identified cause of autism. FXS is caused by transcriptional silencing of the FMR1 gene that encodes the fragile X mental retardation protein (FMRP), but the pathogenesis of the disease is unknown. According to one proposal, many psychiatric and neurological symptoms of FXS result from unchecked activation of mGluR5, a metabotropic glutamate receptor. To test this idea we generated Fmr1 mutant mice with a 50% reduction in mGluR5 expression and studied a range of phenotypes with relevance to the human disorder. Our results demonstrate that mGluR5 contributes significantly to the pathogenesis of the disease, a finding that has significant therapeutic implications for fragile X and related developmental disorders. Limbic Epileptogenesis in a Mouse Model of Fragile X Syndrome. Qiu LF, Lu TJ, Hu XL, Yi YH, Liao WP, Xiong ZQ. Cereb Cortex 2009 in press. (doi:10.1093/cercor/bhn163) Fragile X syndrome (FXS), caused by silencing of the Fmr1 gene, is the most common form of inherited mental retardation. Epilepsy is reported to occur in 20–25% of individuals with FXS. However, no overall increased excitability has been reported in Fmr1 knockout (KO) mice, except for increased sensitivity to auditory stimulation. Here, we report that kindling increased the expressions of Fmr1 mRNA and protein in the forebrain of wild-type (WT) mice. Kindling development was dramatically accelerated in Fmr1 KO mice, and Fmr1 KO mice also displayed prolonged electrographic seizures during kindling and more severe mossy fiber sprouting after kindling. The accelerated rate of kindling was partially repressed by inhibiting N-methyl-D-aspartic acid receptor (NMDAR) with MK-801 or mGluR5 receptor with 2-methyl-6-(phenylethynyl)-pyridine (MPEP). The rate of kindling development in WT was not effected by MPEP, however, suggesting that FMRP normally suppresses epileptogenic signaling downstream of metabotropic glutamate receptors. Our findings reveal that FMRP plays a critical role in suppressing limbic epileptogenesis and predict that the enhanced susceptibility of patients with FXS to epilepsy is a direct consequence of the loss of an important homeostatic factor that mitigates vulnerability to excessive neuronal excitation.

scholarly journals Neuroanatomy of fragile X syndrome is associated with aberrant behavior and the fragile X mental retardation protein (FMRP)

2008 ◽  
Vol 63 (1) ◽  
pp. 40-51 ◽  
Author(s):  
Doron Gothelf ◽  
Joyce A. Furfaro ◽  
Fumiko Hoeft ◽  
Mark A. Eckert ◽  
Scott S. Hall ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Aberrant Behavior ◽  
Fragile X Mental Retardation ◽  
Mental Retardation Protein

scholarly journals FMRP sustains presynaptic function via control of activity-dependent bulk endocytosis

2020 ◽  
Author(s):  
Katherine Bonnycastle ◽  
Peter C. Kind ◽  
Michael A. Cousin
Keyword(s):  
Mental Retardation ◽  
Fragile X Syndrome ◽  
Neuronal Activity ◽  
Neurotransmitter Release ◽  
Fragile X ◽  
High Frequency Stimulation ◽  
Neuronal Cultures ◽  
Fragile X Mental Retardation ◽  
Mental Retardation Protein ◽  
Activity Dependent

ABSTRACTSynaptic vesicle (SV) recycling is essential for the maintenance of neurotransmission, with a number of neurodevelopmental disorders linked to defects in this process. Fragile X syndrome (FXS) results from a loss of fragile X mental retardation protein (FMRP) encoded by the FMR1 gene. FMRP is an established translation repressor, however it also has translation-independent presynaptic roles, including regulation of the trafficking and function of specific ion channels. Since defects in SV recycling are exacerbated during intense neuronal activity, we investigated whether these events were disproportionately affected by the absence of FMRP. We revealed that primary neuronal cultures from a Fmr1 knockout rat model display a specific defect in activity-dependent bulk endocytosis (ADBE). ADBE is dominant during intense neuronal activity, and this defect resulted in an inability of Fmr1 knockout neurons to sustain SV recycling during trains of high frequency stimulation. Using a molecular replacement strategy, we revealed that a human FMRP interaction mutant failed to correct ADBE dysfunction in knockout neurons. Therefore, FMRP performs a key role in sustaining neurotransmitter release via selective control of the endocytosis mode, ADBE.SIGNIFICANCE STATEMENTLoss of fragile X mental retardation protein (FMRP) results in fragile X syndrome (FXS), however whether its loss has a direct role in neurotransmitter release remains a matter of debate. We demonstrate that neurons lacking FMRP display a specific defect in a mechanism that sustains neurotransmitter release during intense neuronal firing, called activity-dependent bulk endocytosis (ADBE). This discovery provides key insights into mechanisms of brain communication that occur due to loss of FMRP function. Importantly it also reveals ADBE as a potential therapeutic target to correct the circuit hyperexcitabilty observed in FXS.

scholarly journals Fragile X mental retardation protein replacement restores hippocampal synaptic function in a mouse model of fragile X syndrome

Gene Therapy ◽  
2009 ◽  
Vol 16 (9) ◽  
pp. 1122-1129 ◽  
Author(s):  
Z Zeier ◽  
A Kumar ◽  
K Bodhinathan ◽  
J A Feller ◽  
T C Foster ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Mouse Model ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Synaptic Function ◽  
Fragile X Mental Retardation ◽  
Mental Retardation Protein
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