Shank protein: Difference between revisions
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Chromosome 22q13 deletion syndrome (22q13DS) is a neurobehavioral syndrome marked by neonatal hyptonia, global developmental delay, and [[Autism|autism spectrum disorder]] features.<ref name="Durand"/> The SHANK3 gene is located within this region of chromosome 22. Studies have revealed that point mutations in SHANK3 can produce the entirety of neurodevelopmental symptoms associated with 22q13DS, accounting for 1% of autism cases.<ref name="Garber">PMID: 17626859</ref> At the molecular level, disruption of the full length Shank3 protein results in reductions in AMPA receptor mediated transmission and spine remodeling.<ref name="Bozdagi"/> Shank3 heterozygous mice, who are haploinsufficient for the Shank3 gene display less social sniffing and emitted fewer ultrasonic vocalizations during interactions with estrus female. Further, knockout mice of Shank have a decreased spine number, a diminished PSD size, decreased levels of GKAP and Homer, and reduced synaptic transmission. Interestingly, overexpression of SHANK3 may also result in an ASD, supporting the hypothesis that Autism is caused by improper Excitatory/Inhibitory neuronal ratios in the brain.<ref name="Bozdagi"/> Measurements of broad miRNA expression levels in Autism patients uncovered dysregulated miRNAs for genes like that of [[MeCP2]], the cause of Rett Syndrome, [[Neurexin-Neuroligin Interaction|NRXN-1]], a gene implicated in ASDs, and Shank3, validating Shank3’s role in autism.<ref>PMID:18563458</ref> Due to the marked reduction in AMPA mediated transmission in Shank3 mutants, compounds that enhance AMPA transmission (AMPAkinses) as potential [[Pharmaceutical Drugs|therapeutic approaches]] to treating some ASDs.<ref name="Bozdagi"/> | Chromosome 22q13 deletion syndrome (22q13DS) is a neurobehavioral syndrome marked by neonatal hyptonia, global developmental delay, and [[Autism|autism spectrum disorder]] features.<ref name="Durand"/> The SHANK3 gene is located within this region of chromosome 22. Studies have revealed that point mutations in SHANK3 can produce the entirety of neurodevelopmental symptoms associated with 22q13DS, accounting for 1% of autism cases.<ref name="Garber">PMID: 17626859</ref> At the molecular level, disruption of the full length Shank3 protein results in reductions in AMPA receptor mediated transmission and spine remodeling.<ref name="Bozdagi"/> Shank3 heterozygous mice, who are haploinsufficient for the Shank3 gene display less social sniffing and emitted fewer ultrasonic vocalizations during interactions with estrus female. Further, knockout mice of Shank have a decreased spine number, a diminished PSD size, decreased levels of GKAP and Homer, and reduced synaptic transmission. Interestingly, overexpression of SHANK3 may also result in an ASD, supporting the hypothesis that Autism is caused by improper Excitatory/Inhibitory neuronal ratios in the brain.<ref name="Bozdagi"/> Measurements of broad miRNA expression levels in Autism patients uncovered dysregulated miRNAs for genes like that of [[MeCP2]], the cause of Rett Syndrome, [[Neurexin-Neuroligin Interaction|NRXN-1]], a gene implicated in ASDs, and Shank3, validating Shank3’s role in autism.<ref>PMID:18563458</ref> Due to the marked reduction in AMPA mediated transmission in Shank3 mutants, compounds that enhance AMPA transmission (AMPAkinses) as potential [[Pharmaceutical Drugs|therapeutic approaches]] to treating some ASDs.<ref name="Bozdagi"/> | ||
BetaPIX belongs to a group of guanine nucleotide exchange factors used by Rho GTPase family members, like Rac1 and Cdc42, which are known to regulate the actin cytoskeleton of synapses.<ref name="IM">PMID: 20117114</ref> PIX has an N-terminal Src homology 3 (SH3) domain which associates with PAK, a coiled-coil (CC) domain, which is critical for multimerization, and a C-terminal PDZ binding domain which interacts with the PDZ domain of Shank.<ref name="IM"/> The interaction of Shank with betaPIX promotes the synaptic localization of betaPIX and betaPIX associated p21 Associated Kinase (PAK). Since PAK is known to regulate the actin cytoskeleton and that dendritic spines are actin-rich structures, it is believed that Shank recruits betaPIX and associated proteins to spines and regulates postsynaptic structure.<ref name="Park"/> | BetaPIX belongs to a group of guanine nucleotide exchange factors used by Rho GTPase family members, like Rac1 and Cdc42, which are known to regulate the actin cytoskeleton of synapses.<ref name="IM">PMID: 20117114</ref> PIX has an N-terminal Src homology 3 (SH3) domain which associates with PAK, a coiled-coil (CC) domain, which is critical for multimerization, and a C-terminal PDZ binding domain which interacts with the PDZ domain of Shank.<ref name="IM"/> The interaction of Shank with betaPIX promotes the synaptic localization of betaPIX and betaPIX associated p21 Associated Kinase (PAK). Since PAK is known to regulate the actin cytoskeleton and that dendritic spines are actin-rich structures, it is believed that Shank recruits betaPIX and associated proteins to spines and regulates postsynaptic structure.<ref name="Park"/> | ||