Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004352 (autism)
 32,579 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since its discovery in 1997, phosphatase and tensin homologue deleted on chromosome 10 (PTEN) has become one of the most important molecules in tumor biology. Mutations, deletions or dysregulation of PTEN is found in many human tumors. Recent studies have extended the reach of PTEN to include diabetes and neurological diseases such as Parkinson's and autism. In this review, we summarize the traditionally characterized function of PTEN as the lipid phosphatase that dephosphorylates PI-3,4,5-P(3), and several other newly discovered functions. The inhibition of the phosphatidylinositol-3-kinase (PI3K)/AKT signaling pathway may account for most of PTEN's tumor suppressing function. However, other growth inhibiting functions of PTEN may not involve this pathway. PTEN can also inhibit growth through its protein phosphatase activity and in ways not related to its enzymatic activity at all. We survey the many functions and biochemical interactions of PTEN in cytoplasm, the nucleus and throughout the cell in this paper.
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PMID:Phosphatase and tensin homologue deleted on chromosome 10: extending its PTENtacles. 1895 Jul 30

Germline mutations in PTEN have been described in a spectrum of syndromes that are collectively known as PTEN hamartoma tumor syndrome (PHTS). In addition to being mutated in the germline in PHTS, somatic loss-of-function PTEN mutations are seen in a wide range of sporadic human tumors. Here, we show evidence of upregulated proteasome activity in PHTS-derived lymphoblasts, Pten knock-in mice and cell lines expressing missense and nonsense PTEN mutations. Notably, elevated nuclear proteasome activity occurred in cells expressing the nuclear mislocalized PTEN-K62R mutant, whereas elevated cytosolic proteasome activity was observed in cells expressing the cytosolic-predominant mutant PTEN (M3M4 and C136R). Treatment with proteasome inhibitor MG-132 was able to restore both nonsense and missense mutant PTEN protein levels in vitro. PHTS patients with destabilizing PTEN mutations and proteasome hyperactivity are more susceptible to develop neurologic symptoms such as mental retardation and autism than mutation-positive patients with normal proteasome activity. A detailed molecular and functional analysis shows that PTEN mutants most likely cause proteasome hyperactivity via 2 different mechanisms, namely, induction of proteotoxic stress and loss of protein phosphatase activity. These results provide novel insights into the cellular functions of PTEN and reveal molecular mechanisms whereby PTEN mutations increase proteasome activity and lead to neurologic phenotypes.
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PMID:Cowden syndrome-related mutations in PTEN associate with enhanced proteasome activity. 2347 34

Mutations in the X-linked CDKL5 (cyclin-dependent kinase-like 5) gene have been associated with several forms of neurodevelopmental disorders, including atypical Rett syndrome, autism spectrum disorders, and early infantile epileptic encephalopathy. Accordingly, loss of CDKL5 in mice results in autistic-like features and impaired neuronal communication. Although the biological functions of CDKL5 remain largely unknown, recent pieces of evidence suggest that CDKL5 is involved in neuronal plasticity. Herein, we show that, at all stages of development, neuronal depolarization induces a rapid increase in CDKL5 levels, mostly mediated by extrasomatic synthesis. In young neurons, this induction is prolonged, whereas in more mature neurons, NMDA receptor stimulation induces a protein phosphatase 1-dependent dephosphorylation of CDKL5 that is mandatory for its proteasome-dependent degradation. As a corollary, neuronal activity leads to a prolonged induction of CDKL5 levels in immature neurons but to a short lasting increase of the kinase in mature neurons. Recent results demonstrate that many genes associated with autism spectrum disorders are crucial components of the activity-dependent signaling networks regulating the composition, shape, and strength of the synapse. Thus, we speculate that CDKL5 deficiency disrupts activity-dependent signaling and the consequent synapse development, maturation, and refinement.
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PMID:Synaptic synthesis, dephosphorylation, and degradation: a novel paradigm for an activity-dependent neuronal control of CDKL5. 2555 10

Sodium potassium chloride co-transporter (NKCC) belongs to cation-dependent chloride co-transporter family, whose activation allows the entry of Na(+), K(+) and 2Cl(-) inside the cell. It acts in concert with K(+) Cl(-) co-transporter (KCC), which extrudes K(+) and Cl(-) ions from cell. NKCC1 is widely distributed throughout the body, while NKCC2 is exclusively present in kidney. Protein kinase A, protein kinase C, Ste20-related proline-alanine-rich kinase, oxidative stress responsive kinases, With No K=lysine kinase and protein phosphatase type 1 control the phosphorylation/dephosphorylation of key threonine residues of in regulatory domain of NKCC1. The selective inhibitors of NKCC1 including bumetanide and furosemide are conventionally employed as diuretics. However, recent studies have indicated that NKCC1 may be involved in the pathophysiology of anxiety, cerebral ischemia, epilepsy, neuropathic pain, fragile X syndrome, autism and schizophrenia. The inhibitors of NKCC1 are shown to produce anxiolytic effects; attenuate cerebral ischemia-induced neuronal injury; produce antiepileptic effects and attenuate neuropathic pain. In the early developing brain, GABAA activation primarily produces excitatory actions due to high NKCC1/KCC2 ratio. However, as the development progresses, the ratio of NKCC1/KCC2 ratio reverses and there is switch in the polarity of GABAA actions and latter acquires the inhibitory actions. The recapitulation of developmental-like state during pathological state may be associated with increase in the expression and functioning of NKCC1, which decreases the strength of inhibitory GABAergic neurotransmission. The present review describes the expanding role and mechanism of NKCC1 in the pathophysiology of different diseases.
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PMID:Expanding Spectrum of Sodium Potassium Chloride Co-transporters in the Pathophysiology of Diseases. 2641 65

Protein Phosphatase 2 Regulatory Subunit B' Delta (PPP2R5D)-related intellectual disability (ID) and neurodevelopmental delay results from germline de novo mutations in the PPP2R5D gene. This gene encodes the protein PPP2R5D (also known as the B56 delta subunit), which is an isoform of the subunit family B56 of the enzyme serine/threonine-protein phosphatase 2A (PP2A). Clinical signs include intellectual disability (ID); autism spectrum disorder (ASD); epilepsy; speech problems; behavioral challenges; and ophthalmologic, skeletal, endocrine, cardiac, and genital malformations. The association of defective PP2A activity in the brain with a wide range of severity of ID, along with its role in ASD, Alzheimer's disease, and Parkinson's-like symptoms, have recently generated the impetus for further research into mutations within this gene. PP2A, together with protein phosphatase 1 (PP1), accounts for more than 90% of all phospho-serine/threonine dephosphorylations in different tissues. The specificity for a wide variety of substrates is determined through nearly 100 different PP2A holoenzymes that are formed by at least 23 types of regulatory B subunits, and two isoforms each of the catalytic subunit C and the structural subunit A. In the mammalian brain, PP2A-mediated protein dephosphorylation plays an important role in learning and memory. The PPP2R5D subunit is highly expressed in the brain and the PPP2A-PPP2R5D holoenzyme plays an important role in maintaining neurons and regulating neuronal signaling. From 2015 to 2017, 25 individuals with PPP2R5D-related developmental disorder were diagnosed. Since then, Whole-Exome Sequencing (WES) has helped to identify more unrelated individuals clinically diagnosed with a neurodevelopmental disorder with pathological variants of PPP2R5D. In this review, we discuss the current understanding of the clinical and genetic aspects of the disorder in the context of the known functions of the PP2A-PPP2R5D holoenzyme in the brain, as well as the pathogenic mutations in PPP2R5D that lead to deficient PP2A-PPP2R5D dephosphorylation and their implications during development and in the etiology of autism, Parkinson's disease, Alzheimer's disease, and so forth. In the future, tools such as transgenic animals carrying pathogenic PPP2R5D mutations, and patient-derived induced pluripotent stem cell lines need to be developed in order to fully understand the effects of these mutations on different neural cell types.
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PMID:PPP2R5D-Related Intellectual Disability and Neurodevelopmental Delay: A Review of the Current Understanding of the Genetics and Biochemical Basis of the Disorder. 3207 98

PTEN is a lipid and protein phosphatase that regulates cell growth and survival. Mutations to PTEN are highly penetrant for autism spectrum disorder (ASD). Here, we briefly review the evidence linking PTEN mutations to ASD and the mouse models that have been used to study the role of PTEN in neurodevelopment. We then focus on the cellular phenotypes associated with PTEN loss in neurons, highlighting the role PTEN plays in neuronal proliferation, migration, survival, morphology, and plasticity.
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PMID:The Role of PTEN in Neurodevelopment. 3239 70

Myosin XVI (Myo16), a vertebrate-specific motor protein, is a recently discovered member of the myosin superfamily. The detailed functionality regarding myosin XVI requires elucidating or clarification; however, it appears to portray an important role in neural development and in the proper functioning of the nervous system. It is expressed in the largest amount in neural tissues in the late embryonic-early postnatal period, specifically the time in which neuronal cell migration and dendritic elaboration coincide. The impaired expression of myosin XVI has been found lurking in the background of several neuropsychiatric disorders including autism, schizophrenia and/or bipolar disorders.Two principal isoforms of class XVI myosins have been thus far described: Myo16a, the tailless cytoplasmic isoform and Myo16b, the full-length molecule featuring both cytoplasmic and nuclear localization. Both isoforms contain a class-specific N-terminal ankyrin repeat domain that binds to the protein phosphatase catalytic subunit. Myo16b, the predominant isoform, exhibits a diverse function. In the cytoplasm, it participates in the reorganization of the actin cytoskeleton through activation of the PI3K pathway and the WAVE-complex, while in the nucleus it may possess a role in cell cycle regulation. Based on the sequence, myosin XVI may have a compromised ATPase activity, implying a potential stationary role.
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PMID:Myosin XVI. 3245 69