Pub Date : 2022-03-01DOI: 10.1080/01677063.2022.2093353
Atsushi Ueda, Tristan C D G O'Harrow, Xiaomin Xing, Salleh Ehaideb, J Robert Manak, Chun-Fang Wu
Previous studies have demonstrated the striking mutational effects of the Drosophila planar cell polarity gene prickle (pk) on larval motor axon microtubule-mediated vesicular transport and on adult epileptic behavior associated with neuronal circuit hyperexcitability. Mutant alleles of the prickle-prickle (pkpk) and prickle-spiny-legs (pksple) isoforms (hereafter referred to as pk and sple alleles, respectively) exhibit differential phenotypes. While both pk and sple affect larval motor axon transport, only sple confers motor circuit and behavior hyperexcitability. However, mutations in the two isoforms apparently counteract to ameliorate adult motor circuit and behavioral hyperexcitability in heteroallelic pkpk/pksple flies. We have further investigated the consequences of altered axonal transport in the development and function of the larval neuromuscular junction (NMJ). We uncovered robust dominant phenotypes in both pk and sple alleles, including synaptic terminal overgrowth (as revealed by anti-HRP and -Dlg immunostaining) and poor vesicle release synchronicity (as indicated by synaptic bouton focal recording). However, we observed recessive alteration of synaptic transmission only in pk/pk larvae, i.e. increased excitatory junctional potential (EJP) amplitude in pk/pk but not in pk/+ or sple/sple. Interestingly, for motor terminal excitability sustained by presynaptic Ca2+ channels, both pk and sple exerted strong effects to produce prolonged depolarization. Notably, only sple acted dominantly whereas pk/+ appeared normal, but was able to suppress the sple phenotypes, i.e. pk/sple appeared normal. Our observations contrast the differential roles of the pk and sple isoforms and highlight their distinct, variable phenotypic expression in the various structural and functional aspects of the larval NMJ.
{"title":"Abnormal larval neuromuscular junction morphology and physiology in <i>Drosophila</i> prickle isoform mutants with known axonal transport defects and adult seizure behavior.","authors":"Atsushi Ueda, Tristan C D G O'Harrow, Xiaomin Xing, Salleh Ehaideb, J Robert Manak, Chun-Fang Wu","doi":"10.1080/01677063.2022.2093353","DOIUrl":"https://doi.org/10.1080/01677063.2022.2093353","url":null,"abstract":"<p><p>Previous studies have demonstrated the striking mutational effects of the <i>Drosophila</i> planar cell polarity gene <i>prickle (pk)</i> on larval motor axon microtubule-mediated vesicular transport and on adult epileptic behavior associated with neuronal circuit hyperexcitability. Mutant alleles of the <i>prickle</i>-<i>prickle</i> (<i>pk<sup>pk</sup></i>) and <i>prickle</i>-<i>spiny-legs</i> (<i>pk<sup>sple</sup></i>) isoforms (hereafter referred to as <i>pk</i> and <i>sple</i> alleles, respectively) exhibit differential phenotypes. While both <i>pk</i> and <i>sple</i> affect larval motor axon transport, only <i>sple</i> confers motor circuit and behavior hyperexcitability. However, mutations in the two isoforms apparently counteract to ameliorate adult motor circuit and behavioral hyperexcitability in heteroallelic <i>pk<sup>pk</sup>/pk<sup>spl</sup></i><sup>e</sup> flies. We have further investigated the consequences of altered axonal transport in the development and function of the larval neuromuscular junction (NMJ). We uncovered robust dominant phenotypes in both <i>pk</i> and <i>sple</i> alleles, including synaptic terminal overgrowth (as revealed by anti-HRP and -Dlg immunostaining) and poor vesicle release synchronicity (as indicated by synaptic bouton focal recording). However, we observed recessive alteration of synaptic transmission only in <i>pk/pk</i> larvae, i.e. increased excitatory junctional potential (EJP) amplitude in <i>pk/pk</i> but not in <i>pk</i>/+ or <i>sple</i>/<i>sple</i>. Interestingly, for motor terminal excitability sustained by presynaptic Ca<sup>2+</sup> channels, both <i>pk</i> and <i>sple</i> exerted strong effects to produce prolonged depolarization. Notably, only <i>sple</i> acted dominantly whereas <i>pk</i>/+ appeared normal, but was able to suppress the <i>sple</i> phenotypes, i.e. <i>pk/sple</i> appeared normal. Our observations contrast the differential roles of the <i>pk</i> and <i>sple</i> isoforms and highlight their distinct, variable phenotypic expression in the various structural and functional aspects of the larval NMJ.</p>","PeriodicalId":16491,"journal":{"name":"Journal of neurogenetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10689881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-03-01Epub Date: 2022-10-13DOI: 10.1080/01677063.2022.2129632
Ashok R Dinasarapu, Diane J Sutcliffe, Fatemeh Seifar, Jasper E Visser, H A Jinnah
Lesch-Nyhan disease (LND) is a neurodevelopmental disorder caused by variants in the HPRT1 gene, which encodes the enzyme hypoxanthine-guanine phosphoribosyl transferase (HGprt). HGprt deficiency provokes numerous metabolic changes which vary among different cell types, making it unclear which changes are most relevant for abnormal neural development. To begin to elucidate the consequences of HGprt deficiency for developing human neurons, neural stem cells (NSCs) were prepared from 6 induced pluripotent stem cell (iPSC) lines from individuals with LND and compared to 6 normal healthy controls. For all 12 lines, gene expression profiles were determined by RNA-seq and protein expression profiles were determined by shotgun proteomics. The LND lines revealed significant changes in expression of multiple genes and proteins. There was little overlap in findings between iPSCs and NSCs, confirming the impact of HGprt deficiency depends on cell type. For NSCs, gene expression studies pointed towards abnormalities in WNT signaling, which is known to play a role in neural development. Protein expression studies pointed to abnormalities in the mitochondrial F0F1 ATPase, which plays a role in maintaining cellular energy. These studies point to some mechanisms that may be responsible for abnormal neural development in LND.
{"title":"Abnormalities of neural stem cells in Lesch-Nyhan disease.","authors":"Ashok R Dinasarapu, Diane J Sutcliffe, Fatemeh Seifar, Jasper E Visser, H A Jinnah","doi":"10.1080/01677063.2022.2129632","DOIUrl":"10.1080/01677063.2022.2129632","url":null,"abstract":"<p><p>Lesch-Nyhan disease (LND) is a neurodevelopmental disorder caused by variants in the <i>HPRT1</i> gene, which encodes the enzyme hypoxanthine-guanine phosphoribosyl transferase (HGprt). HGprt deficiency provokes numerous metabolic changes which vary among different cell types, making it unclear which changes are most relevant for abnormal neural development. To begin to elucidate the consequences of HGprt deficiency for developing human neurons, neural stem cells (NSCs) were prepared from 6 induced pluripotent stem cell (iPSC) lines from individuals with LND and compared to 6 normal healthy controls. For all 12 lines, gene expression profiles were determined by RNA-seq and protein expression profiles were determined by shotgun proteomics. The LND lines revealed significant changes in expression of multiple genes and proteins. There was little overlap in findings between iPSCs and NSCs, confirming the impact of HGprt deficiency depends on cell type. For NSCs, gene expression studies pointed towards abnormalities in WNT signaling, which is known to play a role in neural development. Protein expression studies pointed to abnormalities in the mitochondrial F<sub>0</sub>F<sub>1</sub> ATPase, which plays a role in maintaining cellular energy. These studies point to some mechanisms that may be responsible for abnormal neural development in LND.</p>","PeriodicalId":16491,"journal":{"name":"Journal of neurogenetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9847586/pdf/nihms-1862228.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9464385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-03-01DOI: 10.1080/01677063.2022.2132104
Chun-Fang Wu
The 2021 Nobel Prize in Medicine and Physiology recognized the seminal work of David Julius, who established the temperature and pain sensory mechanisms based on the TRPV channel, and Ardem Patapoutian, who resolved the stretch activation mechanism for touch and proprietary sensation via Piezo channels. We are fortunate and proud to publish a special section on the force-from-lipid principle underlining Piezo channel activation and the origin of the first TRP channel, prepared by the pioneers who initiated the early work that led to the discoveries (Martinac & Kung, 2022; Minke & Pak, 2022). Professors Baruch Minke and William Pak recount the story of their early endeavor to reveal the phototransduction process mediated by the TRP channel in the fruit fly Drosophila. This light-sensitive TRP channel is now recognized as the founding member of the TRP channel superfamily, which encompasses a large category of channels underpinning different sensory mechanisms, including visual, auditory, thermal, and mechanosensory transduction. The functioning of Piezo channels turns out to be based on the same force-from-lipid principle, originating from lipid membrane lateral force without involving any cytoskeletal or cell adhesion molecules. As professors Ching Kung and Boris Martinac recount in their article, the initial finding actually originated from studies on a special strain of giant E. coli. Indeed, ‘what is true for E. coli is true for the elephant’.
{"title":"The origins of the force-from-lipid principle and the founding member of the TRP channel superfamily.","authors":"Chun-Fang Wu","doi":"10.1080/01677063.2022.2132104","DOIUrl":"https://doi.org/10.1080/01677063.2022.2132104","url":null,"abstract":"The 2021 Nobel Prize in Medicine and Physiology recognized the seminal work of David Julius, who established the temperature and pain sensory mechanisms based on the TRPV channel, and Ardem Patapoutian, who resolved the stretch activation mechanism for touch and proprietary sensation via Piezo channels. We are fortunate and proud to publish a special section on the force-from-lipid principle underlining Piezo channel activation and the origin of the first TRP channel, prepared by the pioneers who initiated the early work that led to the discoveries (Martinac & Kung, 2022; Minke & Pak, 2022). Professors Baruch Minke and William Pak recount the story of their early endeavor to reveal the phototransduction process mediated by the TRP channel in the fruit fly Drosophila. This light-sensitive TRP channel is now recognized as the founding member of the TRP channel superfamily, which encompasses a large category of channels underpinning different sensory mechanisms, including visual, auditory, thermal, and mechanosensory transduction. The functioning of Piezo channels turns out to be based on the same force-from-lipid principle, originating from lipid membrane lateral force without involving any cytoskeletal or cell adhesion molecules. As professors Ching Kung and Boris Martinac recount in their article, the initial finding actually originated from studies on a special strain of giant E. coli. Indeed, ‘what is true for E. coli is true for the elephant’.","PeriodicalId":16491,"journal":{"name":"Journal of neurogenetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10709528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-03-01Epub Date: 2022-01-31DOI: 10.1080/01677063.2022.2028784
Xi-Wu Yan, Huai-Jun Liu, Yu-Xing Hong, Ting Meng, Jun Du, Cheng Chang
Alzheimer's disease (AD) is the leading cause of dementia globally, but effective treatment is lacking. We aimed to explore lncRNA XIST role in AD and the mechanisms involved in the effect of changes in lncRNA XIST on the expression of Aβ-degrading enzymes. The mouse model of AD and the cell model induced by Aβ were established. LncRNA XIST, IDE, NEP, Plasmin, ACE, EZH2 expressions and distribution of XIST in the nucleus and cytoplasm were detected by qRT-PCR. Inflammatory cytokines IL-6, IL-1β, TNFα, IL-8, and Aβ42 levels were detected by ELISA. TUNEL was used to measure brain tissue damage. Cell proliferation was detected by CCK-8 assay. Flow cytometry detected cell apoptosis. RIP validated the combination of XIST and EZH2. ChIP verified that XIST recruits EZH2 to mediate enrichment of HEK27me3 in the NEP promoter region. The protein expression in brain tissues and cells was detected by Western blot. The expression of lncRNA XIST was increased in AD mice and cell models. Inflammation and injury of nerve cells occurred in AD mice and cell models. The knockdown of lncRNA XIST alleviated Aβ-induced neuronal inflammation and damage. LncRNA XIST affected the expression of Aβ-degrading enzyme NEP, and lncRNA XIST was negatively correlated with NEP expression in AD mice. LncRNA XIST regulated NEP expression partly through epigenetic regulation by binding with EZH2. LncRNA XIST mediated neuronal inflammation and injury through epigenetic regulation of NEP. Overall, our study found that lncRNA XIST induced Aβ accumulation and neuroinflammation by the epigenetic repression of NEP in AD.
{"title":"lncRNA XIST induces Aβ accumulation and neuroinflammation by the epigenetic repression of NEP in Alzheimer's disease.","authors":"Xi-Wu Yan, Huai-Jun Liu, Yu-Xing Hong, Ting Meng, Jun Du, Cheng Chang","doi":"10.1080/01677063.2022.2028784","DOIUrl":"https://doi.org/10.1080/01677063.2022.2028784","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is the leading cause of dementia globally, but effective treatment is lacking. We aimed to explore lncRNA XIST role in AD and the mechanisms involved in the effect of changes in lncRNA XIST on the expression of Aβ-degrading enzymes. The mouse model of AD and the cell model induced by Aβ were established. LncRNA XIST, IDE, NEP, Plasmin, ACE, EZH2 expressions and distribution of XIST in the nucleus and cytoplasm were detected by qRT-PCR. Inflammatory cytokines IL-6, IL-1β, TNFα, IL-8, and Aβ42 levels were detected by ELISA. TUNEL was used to measure brain tissue damage. Cell proliferation was detected by CCK-8 assay. Flow cytometry detected cell apoptosis. RIP validated the combination of XIST and EZH2. ChIP verified that XIST recruits EZH2 to mediate enrichment of HEK27me3 in the NEP promoter region. The protein expression in brain tissues and cells was detected by Western blot. The expression of lncRNA XIST was increased in AD mice and cell models. Inflammation and injury of nerve cells occurred in AD mice and cell models. The knockdown of lncRNA XIST alleviated Aβ-induced neuronal inflammation and damage. LncRNA XIST affected the expression of Aβ-degrading enzyme NEP, and lncRNA XIST was negatively correlated with NEP expression in AD mice. LncRNA XIST regulated NEP expression partly through epigenetic regulation by binding with EZH2. LncRNA XIST mediated neuronal inflammation and injury through epigenetic regulation of NEP. Overall, our study found that lncRNA XIST induced Aβ accumulation and neuroinflammation by the epigenetic repression of NEP in AD.</p>","PeriodicalId":16491,"journal":{"name":"Journal of neurogenetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39751382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-01-02DOI: 10.1080/01677063.2022.2064462
Ilia M Golomidov, Evgenia M. Latypova, E. Ryabova, O. Bolshakova, A. Komissarov, S. Sarantseva
Abstract Parkinson’s disease (PD) is a neurodegenerative disease characterised by the formation of Lewy bodies and progressive loss of dopaminergic (DA) neurons in the substantia nigra. Lewy bodies mainly consist of α-synuclein, which plays a critical role in the pathophysiology of PD. The α-synuclein is encoded by the SNCA gene and is the first identified gene associated with hereditary PD. Currently, there are at least six disease-associated mutations in α-synuclein that cause dominantly inherited familial forms of PD. Targeted expression of human SNCA.WT/SNCA.A30P/SNCA.A53T gene in Drosophila melanogaster over specific times employing a temperature-dependent UAS/GAL4 – GAL80 system allows for the evaluation of neurodegenerative processes. In this study, SNCA was expressed only in the adult stage of Drosophila development for 1 or 2 weeks, followed by repression of gene expression for the rest of the fly’s life. It was demonstrated that the level of pathology significantly depends on the duration of α-synuclein expression. SNCA gene expression over a longer period of time caused the death of DA neurons, decreased levels of dopamine and locomotor ability. In this case, the observed neurodegenerative processes correlated with the accumulation of α-synuclein in the Drosophila brain. Importantly, repression of α-synuclein expression led to elimination of the soluble protein fraction, in contrast to the insoluble fraction. No further significant development of characteristic signs of pathology was observed after the α-synuclein expression was blocked. Thus, we suggest that reduction of α-synuclein expression alone contributes to slowing down the development of PD-like symptoms.
{"title":"Reduction of the α-synuclein expression promotes slowing down early neuropathology development in the Drosophila model of Parkinson’s disease","authors":"Ilia M Golomidov, Evgenia M. Latypova, E. Ryabova, O. Bolshakova, A. Komissarov, S. Sarantseva","doi":"10.1080/01677063.2022.2064462","DOIUrl":"https://doi.org/10.1080/01677063.2022.2064462","url":null,"abstract":"Abstract Parkinson’s disease (PD) is a neurodegenerative disease characterised by the formation of Lewy bodies and progressive loss of dopaminergic (DA) neurons in the substantia nigra. Lewy bodies mainly consist of α-synuclein, which plays a critical role in the pathophysiology of PD. The α-synuclein is encoded by the SNCA gene and is the first identified gene associated with hereditary PD. Currently, there are at least six disease-associated mutations in α-synuclein that cause dominantly inherited familial forms of PD. Targeted expression of human SNCA.WT/SNCA.A30P/SNCA.A53T gene in Drosophila melanogaster over specific times employing a temperature-dependent UAS/GAL4 – GAL80 system allows for the evaluation of neurodegenerative processes. In this study, SNCA was expressed only in the adult stage of Drosophila development for 1 or 2 weeks, followed by repression of gene expression for the rest of the fly’s life. It was demonstrated that the level of pathology significantly depends on the duration of α-synuclein expression. SNCA gene expression over a longer period of time caused the death of DA neurons, decreased levels of dopamine and locomotor ability. In this case, the observed neurodegenerative processes correlated with the accumulation of α-synuclein in the Drosophila brain. Importantly, repression of α-synuclein expression led to elimination of the soluble protein fraction, in contrast to the insoluble fraction. No further significant development of characteristic signs of pathology was observed after the α-synuclein expression was blocked. Thus, we suggest that reduction of α-synuclein expression alone contributes to slowing down the development of PD-like symptoms.","PeriodicalId":16491,"journal":{"name":"Journal of neurogenetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2022-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42383867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Abstract It has been widely reported that dysregulated long-chain noncoding RNAs (lncRNAs) are closely associated with epilepsy. This study aimed to probe the function of lncRNA growth arrest-specific 5 (GAS5), microRNA (miR)-219 and Calmodulin-dependent protein kinase II (CaMKII)γ/N-methyl-D-aspartate receptor (NMDAR) pathway in epilepsy. Epileptic cell and animal models were constructed using magnesium deficiency treatment and diazepam injection, respectively. GAS5 and miR-219 expressions in epileptic cell and animal models were determined using qRT-PCR assay. The protein levels of CaMKIIγ, NMDAR and apoptosis-related proteins levels were assessed by western blot. Cell counting kit-8 (CCK-8) assay was employed to determine cell proliferation. Besides, TNFα, IL-1β, IL-6 and IL-8 levels were analyzed using enzyme-linked immunosorbent assay (ELISA). Furthermore, cell apoptosis was evaluated using TUNEL staining and flow cytometric analysis. Finally, the binding relationship between GAS5 and EZH2 was verified using RIP and ChIP assay. Our results revealed that GAS5 was markedly upregulated in epileptic cell and animal models, while miR-219 was down-regulated. GAS5 knockdown dramatically increased cell proliferation of epileptic cells, whereas suppressed inflammation and the apoptosis. Furthermore, our results showed that GAS5 epigenetically suppressed transcriptional miR-219 expression via binding to EZH2. miR-219 mimics significantly enhanced cell proliferation of epileptic cells, while inhibited inflammation and the apoptosis, which was neutralized by CaMKIIγ overexpression. Finally, miR-219 inhibition reversed the effects of GAS5 silence on epileptic cells, which was eliminated by CaMKIIγ inhibition. In conclusion, GAS5 affected inflammatory response and cell apoptosis of epilepsy via inhibiting miR-219 and further regulating CaMKIIγ/NMDAR pathway (See graphic summary in Supplementary Material).
{"title":"LncRNA GAS5 promotes epilepsy progression through the epigenetic repression of miR-219, in turn affecting CaMKIIγ/NMDAR pathway","authors":"Chen-sheng Zhao, Dong-xing Liu, Yanping Fan, Jian-kun Wu","doi":"10.1080/01677063.2022.2067536","DOIUrl":"https://doi.org/10.1080/01677063.2022.2067536","url":null,"abstract":"Abstract It has been widely reported that dysregulated long-chain noncoding RNAs (lncRNAs) are closely associated with epilepsy. This study aimed to probe the function of lncRNA growth arrest-specific 5 (GAS5), microRNA (miR)-219 and Calmodulin-dependent protein kinase II (CaMKII)γ/N-methyl-D-aspartate receptor (NMDAR) pathway in epilepsy. Epileptic cell and animal models were constructed using magnesium deficiency treatment and diazepam injection, respectively. GAS5 and miR-219 expressions in epileptic cell and animal models were determined using qRT-PCR assay. The protein levels of CaMKIIγ, NMDAR and apoptosis-related proteins levels were assessed by western blot. Cell counting kit-8 (CCK-8) assay was employed to determine cell proliferation. Besides, TNFα, IL-1β, IL-6 and IL-8 levels were analyzed using enzyme-linked immunosorbent assay (ELISA). Furthermore, cell apoptosis was evaluated using TUNEL staining and flow cytometric analysis. Finally, the binding relationship between GAS5 and EZH2 was verified using RIP and ChIP assay. Our results revealed that GAS5 was markedly upregulated in epileptic cell and animal models, while miR-219 was down-regulated. GAS5 knockdown dramatically increased cell proliferation of epileptic cells, whereas suppressed inflammation and the apoptosis. Furthermore, our results showed that GAS5 epigenetically suppressed transcriptional miR-219 expression via binding to EZH2. miR-219 mimics significantly enhanced cell proliferation of epileptic cells, while inhibited inflammation and the apoptosis, which was neutralized by CaMKIIγ overexpression. Finally, miR-219 inhibition reversed the effects of GAS5 silence on epileptic cells, which was eliminated by CaMKIIγ inhibition. In conclusion, GAS5 affected inflammatory response and cell apoptosis of epilepsy via inhibiting miR-219 and further regulating CaMKIIγ/NMDAR pathway (See graphic summary in Supplementary Material).","PeriodicalId":16491,"journal":{"name":"Journal of neurogenetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2022-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45916724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-01-02DOI: 10.1080/01677063.2022.2064463
Sundarapandian Narendiran, M. Debnath, S. Shivaram, Ramakrishnan Kannan, Shivani Sharma, R. Christopher, D. Seshagiri, S. Jain, M. Purushottam, Sandhya Mangalore, R. Bharath, P. Bindu, S. Sinha, A. Taly, M. Nagappa
Abstract The Hereditary Spastic Paraplegias (HSPs) are a group of clinically and genetically heterogeneous disorders characterized by length dependent degeneration of the corticospinal tracts. Genetic data related to HSPs are limited from India. We aimed to comprehensively analyse the phenotypic characteristics and genetic basis of a large cohort of HSP from India. Patients with HSP phenotype were evaluated for their clinical features, electrophysiological and radiological abnormalities. Genetic analyses were carried out by clinical exome sequencing (n = 52) and targeted sequencing (n = 5). The cohort comprised of 57 probands (M:F 40:17, age: 3.5–49 years). Based on the phenotype, the cohort could be categorized as ‘pure’ (n = 15, 26.3%) and ‘complicated’ (n = 42, 73.7%) HSP. Brain MRI showed thin corpus callosum (n = 10), periventricular hyperintensities (n = 20), cerebral atrophy (n = 3), cerebellar atrophy (n = 3) and diffuse atrophy (n = 4). Sixty-seven variants representing 40 genes were identified including 47 novel variants. Forty-eight patients (84.2%) had variants in genes previously implicated in HSP and other spastic paraplegia syndromes (SPG genes = 24, non-SPG genes = 24); among these 13 had variations in more than one gene and 12 patients (21.0%) had variations in genes implicated in potentially treatable/modifiable metabolic disorders (MTHFR = 8, MTRR = 1, ARG1 = 2 and ABCD1 = 1). In nine patients, no genetic variants implicated in spastic paraplegia phenotype were identified. Thus, the present study from India highlights the phenotypic complexities and spectrum of genetic variations in patients with HSP including those implicated in metabolically modifiable disorders. It sets a platform for carrying out functional studies to validate the causal role of the novel variants and variants of uncertain significance.
{"title":"Novel insights into the genetic profile of hereditary spastic paraplegia in India","authors":"Sundarapandian Narendiran, M. Debnath, S. Shivaram, Ramakrishnan Kannan, Shivani Sharma, R. Christopher, D. Seshagiri, S. Jain, M. Purushottam, Sandhya Mangalore, R. Bharath, P. Bindu, S. Sinha, A. Taly, M. Nagappa","doi":"10.1080/01677063.2022.2064463","DOIUrl":"https://doi.org/10.1080/01677063.2022.2064463","url":null,"abstract":"Abstract The Hereditary Spastic Paraplegias (HSPs) are a group of clinically and genetically heterogeneous disorders characterized by length dependent degeneration of the corticospinal tracts. Genetic data related to HSPs are limited from India. We aimed to comprehensively analyse the phenotypic characteristics and genetic basis of a large cohort of HSP from India. Patients with HSP phenotype were evaluated for their clinical features, electrophysiological and radiological abnormalities. Genetic analyses were carried out by clinical exome sequencing (n = 52) and targeted sequencing (n = 5). The cohort comprised of 57 probands (M:F 40:17, age: 3.5–49 years). Based on the phenotype, the cohort could be categorized as ‘pure’ (n = 15, 26.3%) and ‘complicated’ (n = 42, 73.7%) HSP. Brain MRI showed thin corpus callosum (n = 10), periventricular hyperintensities (n = 20), cerebral atrophy (n = 3), cerebellar atrophy (n = 3) and diffuse atrophy (n = 4). Sixty-seven variants representing 40 genes were identified including 47 novel variants. Forty-eight patients (84.2%) had variants in genes previously implicated in HSP and other spastic paraplegia syndromes (SPG genes = 24, non-SPG genes = 24); among these 13 had variations in more than one gene and 12 patients (21.0%) had variations in genes implicated in potentially treatable/modifiable metabolic disorders (MTHFR = 8, MTRR = 1, ARG1 = 2 and ABCD1 = 1). In nine patients, no genetic variants implicated in spastic paraplegia phenotype were identified. Thus, the present study from India highlights the phenotypic complexities and spectrum of genetic variations in patients with HSP including those implicated in metabolically modifiable disorders. It sets a platform for carrying out functional studies to validate the causal role of the novel variants and variants of uncertain significance.","PeriodicalId":16491,"journal":{"name":"Journal of neurogenetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2022-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43417024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-09-01Epub Date: 2021-07-14DOI: 10.1080/01677063.2021.1950713
Anders Vesterberg, Rudy Rizkalla, Mark J Fitzpatrick
Deciding whether or not to lay an egg on a given substrate is an important task undertaken by females of many arthropods. It involves perceiving the environment (e.g. quality of the substrate, temperature, and humidity), formulating a decision, and then conducting the appropriate behaviours to oviposit. This oviposition site selection (OSS) provides a useful system for studying simple decision-making. OSS in fruit flies, Drosophila melanogaster, is influenced by both genetic and environmental variation. Naturally occurring allelic variation in the foraging gene (for) is known to affect OSS. Given a choice of high- and low-nutrient oviposition substrates, groups of rovers (forR) are known to lay significantly more of their eggs on low-nutrient sites than sitters (fors) and sitter mutants (fors2). Here we ask three questions: (1) Is the role of for in OSS affected by the availability of alternate oviposition sites? (2) Is the role of for in OSS sensitive to the density of ovipositing females? and (3) Does the gustatory sensation of yeast play a role in for-mediated variation in OSS? We find a role of choice and female density in rover/sitter differences in OSS, as well as a role of for in response to glycerol, an indicator of yeast. The role of for in OSS decision-making is complex and multi-faceted and should prove fertile ground for further research into the factors affecting decision-making behaviours.
{"title":"Environmental influences on <i>for</i>-mediated oviposition decisions in <i>Drosophila melanogaster</i>.","authors":"Anders Vesterberg, Rudy Rizkalla, Mark J Fitzpatrick","doi":"10.1080/01677063.2021.1950713","DOIUrl":"https://doi.org/10.1080/01677063.2021.1950713","url":null,"abstract":"<p><p>Deciding whether or not to lay an egg on a given substrate is an important task undertaken by females of many arthropods. It involves perceiving the environment (e.g. quality of the substrate, temperature, and humidity), formulating a decision, and then conducting the appropriate behaviours to oviposit. This oviposition site selection (OSS) provides a useful system for studying simple decision-making. OSS in fruit flies, <i>Drosophila melanogaster</i>, is influenced by both genetic and environmental variation. Naturally occurring allelic variation in the <i>foraging</i> gene (<i>for</i>) is known to affect OSS. Given a choice of high- and low-nutrient oviposition substrates, groups of rovers (<i>for</i><sup>R</sup>) are known to lay significantly more of their eggs on low-nutrient sites than sitters (<i>for</i><sup>s</sup>) and sitter mutants (<i>for</i><sup>s2</sup>). Here we ask three questions: (1) Is the role of <i>for</i> in OSS affected by the availability of alternate oviposition sites? (2) Is the role of <i>for</i> in OSS sensitive to the density of ovipositing females? and (3) Does the gustatory sensation of yeast play a role in <i>for</i>-mediated variation in OSS? We find a role of choice and female density in rover/sitter differences in OSS, as well as a role of <i>for</i> in response to glycerol, an indicator of yeast. The role of <i>for</i> in OSS decision-making is complex and multi-faceted and should prove fertile ground for further research into the factors affecting decision-making behaviours.</p>","PeriodicalId":16491,"journal":{"name":"Journal of neurogenetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2021-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/01677063.2021.1950713","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39182102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-09-01Epub Date: 2021-10-20DOI: 10.1080/01677063.2021.1989425
Sooin Jang, Ji Chen, Jaekyun Choi, Seung Yeon Lim, Hyejin Song, Hyungjun Choi, Hyung Wook Kwon, Min Sung Choi, Jae Young Kwon
The digestion of food and absorption of nutrients occurs in the gut. The nutritional value of food and its nutrients is detected by enteroendocrine cells, and peptide hormones produced by the enteroendocrine cells are thought to be involved in metabolic homeostasis, but the specific mechanisms are still elusive. The enteroendocrine cells are scattered over the entire gastrointestinal tract and can be classified according to the hormones they produce. We followed the changes in combinatorial expression of regulatory peptides in the enteroendocrine cells during metamorphosis from the larva to the adult fruit fly, and re-confirmed the diverse composition of enteroendocrine cell populations. Drosophila enteroendocrine cells appear to differentially regulate peptide expression spatially and temporally depending on midgut region and developmental stage. In the late pupa, Notch activity is known to determine which peptides are expressed in mature enteroendocrine cells of the posterior midgut, and we found that the loss of Notch activity in the anterior midgut results in classes of enteroendocrine cells distinct from the posterior midgut. These results suggest that enteroendocrine cells that populate the fly midgut can differentiate into distinct subtypes that express different combinations of peptides, which likely leads to functional variety depending on specific needs.
{"title":"Spatiotemporal organization of enteroendocrine peptide expression in <i>Drosophila</i>.","authors":"Sooin Jang, Ji Chen, Jaekyun Choi, Seung Yeon Lim, Hyejin Song, Hyungjun Choi, Hyung Wook Kwon, Min Sung Choi, Jae Young Kwon","doi":"10.1080/01677063.2021.1989425","DOIUrl":"https://doi.org/10.1080/01677063.2021.1989425","url":null,"abstract":"<p><p>The digestion of food and absorption of nutrients occurs in the gut. The nutritional value of food and its nutrients is detected by enteroendocrine cells, and peptide hormones produced by the enteroendocrine cells are thought to be involved in metabolic homeostasis, but the specific mechanisms are still elusive. The enteroendocrine cells are scattered over the entire gastrointestinal tract and can be classified according to the hormones they produce. We followed the changes in combinatorial expression of regulatory peptides in the enteroendocrine cells during metamorphosis from the larva to the adult fruit fly, and re-confirmed the diverse composition of enteroendocrine cell populations. <i>Drosophila</i> enteroendocrine cells appear to differentially regulate peptide expression spatially and temporally depending on midgut region and developmental stage. In the late pupa, Notch activity is known to determine which peptides are expressed in mature enteroendocrine cells of the posterior midgut, and we found that the loss of Notch activity in the anterior midgut results in classes of enteroendocrine cells distinct from the posterior midgut. These results suggest that enteroendocrine cells that populate the fly midgut can differentiate into distinct subtypes that express different combinations of peptides, which likely leads to functional variety depending on specific needs.</p>","PeriodicalId":16491,"journal":{"name":"Journal of neurogenetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2021-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39560156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-09-01Epub Date: 2021-05-16DOI: 10.1080/01677063.2021.1905639
Jeffrey S Dason, Marla B Sokolowski
A cGMP-dependent protein kinase (PKG) encoded by the Drosophila foraging (for) gene regulates both synaptic structure (nerve terminal growth) and function (neurotransmission) through independent mechanisms at the Drosophila larval neuromuscular junction (nmj). Glial for is known to restrict nerve terminal growth, whereas presynaptic for inhibits synaptic vesicle (SV) exocytosis during low frequency stimulation. Presynaptic for also facilitates SV endocytosis during high frequency stimulation. for's effects on neurotransmission can occur independent of any changes in nerve terminal growth. However, it remains unclear if for's effects on neurotransmission affect nerve terminal growth. Furthermore, it's possible that for's effects on synaptic structure contribute to changes in neurotransmission. In the present study, we examined these questions using RNA interference to selectively knockdown for in presynaptic neurons or glia at the Drosophila larval nmj. Consistent with our previous findings, presynaptic knockdown of for impaired SV endocytosis, whereas knockdown of glial for had no effect on SV endocytosis. Surprisingly, we found that knockdown of either presynaptic or glial for increased neurotransmitter release in response to low frequency stimulation. Knockdown of presynaptic for did not affect nerve terminal growth, demonstrating that for's effects on neurotransmission does not alter nerve terminal growth. In contrast, knockdown of glial for enhanced nerve terminal growth. This enhanced nerve terminal growth was likely the cause of the enhanced neurotransmitter release seen following knockdown of glial for. Overall, we show that for can affect neurotransmitter release by regulating both synaptic structure and function.
{"title":"A cGMP-dependent protein kinase, encoded by the <i>Drosophila foraging</i> gene, regulates neurotransmission through changes in synaptic structure and function.","authors":"Jeffrey S Dason, Marla B Sokolowski","doi":"10.1080/01677063.2021.1905639","DOIUrl":"https://doi.org/10.1080/01677063.2021.1905639","url":null,"abstract":"<p><p>A cGMP-dependent protein kinase (PKG) encoded by the <i>Drosophila foraging</i> (<i>for</i>) gene regulates both synaptic structure (nerve terminal growth) and function (neurotransmission) through independent mechanisms at the <i>Drosophila</i> larval neuromuscular junction (nmj). Glial <i>for</i> is known to restrict nerve terminal growth, whereas presynaptic <i>for</i> inhibits synaptic vesicle (SV) exocytosis during low frequency stimulation. Presynaptic <i>for</i> also facilitates SV endocytosis during high frequency stimulation. <i>for</i>'s effects on neurotransmission can occur independent of any changes in nerve terminal growth. However, it remains unclear if <i>for</i>'s effects on neurotransmission affect nerve terminal growth. Furthermore, it's possible that <i>for</i>'s effects on synaptic structure contribute to changes in neurotransmission. In the present study, we examined these questions using RNA interference to selectively knockdown <i>for</i> in presynaptic neurons or glia at the <i>Drosophila</i> larval nmj. Consistent with our previous findings, presynaptic knockdown of <i>for</i> impaired SV endocytosis, whereas knockdown of glial <i>for</i> had no effect on SV endocytosis. Surprisingly, we found that knockdown of either presynaptic or glial <i>for</i> increased neurotransmitter release in response to low frequency stimulation. Knockdown of presynaptic <i>for</i> did not affect nerve terminal growth, demonstrating that <i>for</i>'s effects on neurotransmission does not alter nerve terminal growth. In contrast, knockdown of glial <i>for</i> enhanced nerve terminal growth. This enhanced nerve terminal growth was likely the cause of the enhanced neurotransmitter release seen following knockdown of glial <i>for</i>. Overall, we show that <i>for</i> can affect neurotransmitter release by regulating both synaptic structure and function.</p>","PeriodicalId":16491,"journal":{"name":"Journal of neurogenetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2021-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/01677063.2021.1905639","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38990929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}