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Uloga proteina ATP13A2/PARK9 u lizosomskom putu razgradnje u neurodegeneraciji
No full textLysosomes are essential for maintaining neuronal homeostasis through degradation of damaged organelles and misfolded and accumulated proteins. Increasing evidence implicates lysosomal dysfunction in several neurodegenerative disorders, including Parkinson, Alzheimer and Huntington disease. In addition, more than two-thirds of lysosomal storage diseases are exhibiting dysfunction in the central nervous system, emphasizing how neurons are particularly vulnerable to lysosomal impairment. In order to more directly examine the lysosomal function in neurodegeneration it is particularly informative to study neurodegenerative diseases that are caused by mutations in lysosomal proteins. One such disease is Kufor-Rakeb syndrome that is caused by loss-of-function mutations in the lysosomal protein ATP13A2/PARK9 and characterized by early-onset parkinsonism with pyramidal degeneration and dementia. While previous data implicate ATP13A2 in α-synuclein misfolding and toxicity (a protein involved in pathogenesis of Parkinson disease and related synucleinopathies), the underlying mechanism and biological function of ATP13A2 have not been established. We found that loss of ATP13A2 function leads to accumulation of enlarged lysosomes, impaired lysosomal turnover of autophagic vesicles and impaired lysosomal degradation capacity. This lysosomal dysfunction results in preferential accumulation of α-synuclein and toxicity in neurons. Importantly, depletion of endogenous α-synuclein attenuated the toxicity in ATP13A2-deficient neurons, suggesting that loss of ATP13A2 mediates neurotoxicity at least partially via lysosomal dysfunction and consequent accumulation of α-synuclein. In addition, silencing of ATP13A2 in the Caenorhabditis elegans model of Parkinson disease has enhanced α-synuclein mediated degeneration of dopaminergic neurons, further underscoring the functional link between ATP13A2 and α-synuclein in neurodegeneration. Furthermore, in order to elucidate a normal biological function of ATP13A2 protein we identified its interacting partners that revealed putative role for ATP13A2 in vesicular trafficking and fusion. Importantly, a subset of these interactors was modifiers of α-synuclein aggregation and neurotoxicity in Caenorhabditis elegans, further supporting a functional link between ATP13A2 and α-synuclein.
Our findings implicate lysosomal dysfunction and α-synuclein accumulation in the pathogenesis of Kufor-Rakeb syndrome and suggest that upregulation of lysosomal function and downregulation of α-synuclein represent promising therapeutic strategies for this disorder.Lizosomi su važni za održavanje neuronske homeostaze kroz razgradnju oštećenih organela i nakupljenih proteina. Brojni dokazi ukazuju na postojanje lizosomske disfunkcije u nekoliko neurodegenerativnih bolesti, uključujući Parkinsonovu, Alzheimerovu i Huntingtonovu bolest. Nadalje, više od dvije-trećine lizosomskih bolesti odlaganja okarakterizirane su poremećajima središnjeg živčanog sustava, što pokazuje da su neuroni posebno osjetljivi na lizosomske nepravilnosti. Kako bi smo što detaljnije ispitali lizosomsku funkciju u neurodegeneraciji vrlo je značajno istražiti neurodegenerativne bolesti uzrokovane mutacijama u lizosomskim proteinima. Jedna od tih bolesti je i Kufor-Rakeb sindrom koji je uzrokovan mutacijama u lizosomskom proteinu ATP13A2/PARK9 i okarakteriziran kao juvenilni parkinsonizam s piramidalnom degeneracijom i demencijom. Prijašnja otkrića sugeriraju da ATP13A2 ima važnu ulogu u nepravilnom smatanju i toksičnosti α-sinukleina (proteina uključenog u Parkinsonovu bolest i slične sinukleinopatije), no biološka funkcija proteina ATP13A2 kao ni mehanizam povezanosti proteina ATP13A2 i α-sinukleina još nisu poznati. Našim istraživanjem otkrili smo da gubitak funkcije ATP13A2 dovodi do nakupljanja povećanih lizosoma, poremećene lizosomske razgradnje proteina i autofagosoma. Ova lizosomska disfunkcija rezultira nakupljanje α-sinukleina i smrću neurona. Ujedno, utišavanje endogenog α-sinukleina smanjilo je toksičnost u neuronima s utišanim ATP13A2 genom, što sugerira da je neurotoksičnost uzrokovana gubitkom ATP13A2 jednim dijelom posredovana disfunkcijom lizosoma i akumulacijom α-sinukleina. Osim toga, utišavanje ATP13A2 u Caenorhabditis elegans modelu za Parkinsonovu bolest pojačalo je α-sinuklein-posredovanu degeneraciju dopaminskih neurona, što dodatno upućuje na funkcionalnu povezanost između ATP13A2 i α-sinukleina u procesu nerodegeneracije. Nadalje, kako bismo rasvijetlili znanje o normalnoj biološkoj funkciji ATP13A2 proteina, identificirali smo njegove inter-reagirajuće partnere koji su pokazali da ATP13A2 igra ulogu u procesima prijenosa i stapanja vezikula. Značajno je spomenuti i da su pojedini interaktori povećali nakupljanje i neurotoksičnost α-sinukleina u Caenorhabditis elegans, što je pružilo daljne dokaze o funkcionalnoj povezanosti ATP13A2 i α-sinukleina.
Naša otkrića impliciraju lizosomsku disfunkciju i nakupljanje α-sinukleina kao važne elemente u patogenezi Kufor-Rakeb sindroma te ukazuju na to da pojačavanje funkcije lizosoma i smanjivanje razine α-sinukleina predstavljaju obećavajuće terapijske strategije za ovu bolest
Uloga proteina ATP13A2/PARK9 u lizosomskom putu razgradnje u neurodegeneraciji
No full textLysosomes are essential for maintaining neuronal homeostasis through degradation of damaged organelles and misfolded and accumulated proteins. Increasing evidence implicates lysosomal dysfunction in several neurodegenerative disorders, including Parkinson, Alzheimer and Huntington disease. In addition, more than two-thirds of lysosomal storage diseases are exhibiting dysfunction in the central nervous system, emphasizing how neurons are particularly vulnerable to lysosomal impairment. In order to more directly examine the lysosomal function in neurodegeneration it is particularly informative to study neurodegenerative diseases that are caused by mutations in lysosomal proteins. One such disease is Kufor-Rakeb syndrome that is caused by loss-of-function mutations in the lysosomal protein ATP13A2/PARK9 and characterized by early-onset parkinsonism with pyramidal degeneration and dementia. While previous data implicate ATP13A2 in α-synuclein misfolding and toxicity (a protein involved in pathogenesis of Parkinson disease and related synucleinopathies), the underlying mechanism and biological function of ATP13A2 have not been established. We found that loss of ATP13A2 function leads to accumulation of enlarged lysosomes, impaired lysosomal turnover of autophagic vesicles and impaired lysosomal degradation capacity. This lysosomal dysfunction results in preferential accumulation of α-synuclein and toxicity in neurons. Importantly, depletion of endogenous α-synuclein attenuated the toxicity in ATP13A2-deficient neurons, suggesting that loss of ATP13A2 mediates neurotoxicity at least partially via lysosomal dysfunction and consequent accumulation of α-synuclein. In addition, silencing of ATP13A2 in the Caenorhabditis elegans model of Parkinson disease has enhanced α-synuclein mediated degeneration of dopaminergic neurons, further underscoring the functional link between ATP13A2 and α-synuclein in neurodegeneration. Furthermore, in order to elucidate a normal biological function of ATP13A2 protein we identified its interacting partners that revealed putative role for ATP13A2 in vesicular trafficking and fusion. Importantly, a subset of these interactors was modifiers of α-synuclein aggregation and neurotoxicity in Caenorhabditis elegans, further supporting a functional link between ATP13A2 and α-synuclein.
Our findings implicate lysosomal dysfunction and α-synuclein accumulation in the pathogenesis of Kufor-Rakeb syndrome and suggest that upregulation of lysosomal function and downregulation of α-synuclein represent promising therapeutic strategies for this disorder.Lizosomi su važni za održavanje neuronske homeostaze kroz razgradnju oštećenih organela i nakupljenih proteina. Brojni dokazi ukazuju na postojanje lizosomske disfunkcije u nekoliko neurodegenerativnih bolesti, uključujući Parkinsonovu, Alzheimerovu i Huntingtonovu bolest. Nadalje, više od dvije-trećine lizosomskih bolesti odlaganja okarakterizirane su poremećajima središnjeg živčanog sustava, što pokazuje da su neuroni posebno osjetljivi na lizosomske nepravilnosti. Kako bi smo što detaljnije ispitali lizosomsku funkciju u neurodegeneraciji vrlo je značajno istražiti neurodegenerativne bolesti uzrokovane mutacijama u lizosomskim proteinima. Jedna od tih bolesti je i Kufor-Rakeb sindrom koji je uzrokovan mutacijama u lizosomskom proteinu ATP13A2/PARK9 i okarakteriziran kao juvenilni parkinsonizam s piramidalnom degeneracijom i demencijom. Prijašnja otkrića sugeriraju da ATP13A2 ima važnu ulogu u nepravilnom smatanju i toksičnosti α-sinukleina (proteina uključenog u Parkinsonovu bolest i slične sinukleinopatije), no biološka funkcija proteina ATP13A2 kao ni mehanizam povezanosti proteina ATP13A2 i α-sinukleina još nisu poznati. Našim istraživanjem otkrili smo da gubitak funkcije ATP13A2 dovodi do nakupljanja povećanih lizosoma, poremećene lizosomske razgradnje proteina i autofagosoma. Ova lizosomska disfunkcija rezultira nakupljanje α-sinukleina i smrću neurona. Ujedno, utišavanje endogenog α-sinukleina smanjilo je toksičnost u neuronima s utišanim ATP13A2 genom, što sugerira da je neurotoksičnost uzrokovana gubitkom ATP13A2 jednim dijelom posredovana disfunkcijom lizosoma i akumulacijom α-sinukleina. Osim toga, utišavanje ATP13A2 u Caenorhabditis elegans modelu za Parkinsonovu bolest pojačalo je α-sinuklein-posredovanu degeneraciju dopaminskih neurona, što dodatno upućuje na funkcionalnu povezanost između ATP13A2 i α-sinukleina u procesu nerodegeneracije. Nadalje, kako bismo rasvijetlili znanje o normalnoj biološkoj funkciji ATP13A2 proteina, identificirali smo njegove inter-reagirajuće partnere koji su pokazali da ATP13A2 igra ulogu u procesima prijenosa i stapanja vezikula. Značajno je spomenuti i da su pojedini interaktori povećali nakupljanje i neurotoksičnost α-sinukleina u Caenorhabditis elegans, što je pružilo daljne dokaze o funkcionalnoj povezanosti ATP13A2 i α-sinukleina.
Naša otkrića impliciraju lizosomsku disfunkciju i nakupljanje α-sinukleina kao važne elemente u patogenezi Kufor-Rakeb sindroma te ukazuju na to da pojačavanje funkcije lizosoma i smanjivanje razine α-sinukleina predstavljaju obećavajuće terapijske strategije za ovu bolest
Uloga proteina ATP13A2/PARK9 u lizosomskom putu razgradnje u neurodegeneraciji
No full textLysosomes are essential for maintaining neuronal homeostasis through degradation of damaged organelles and misfolded and accumulated proteins. Increasing evidence implicates lysosomal dysfunction in several neurodegenerative disorders, including Parkinson, Alzheimer and Huntington disease. In addition, more than two-thirds of lysosomal storage diseases are exhibiting dysfunction in the central nervous system, emphasizing how neurons are particularly vulnerable to lysosomal impairment. In order to more directly examine the lysosomal function in neurodegeneration it is particularly informative to study neurodegenerative diseases that are caused by mutations in lysosomal proteins. One such disease is Kufor-Rakeb syndrome that is caused by loss-of-function mutations in the lysosomal protein ATP13A2/PARK9 and characterized by early-onset parkinsonism with pyramidal degeneration and dementia. While previous data implicate ATP13A2 in α-synuclein misfolding and toxicity (a protein involved in pathogenesis of Parkinson disease and related synucleinopathies), the underlying mechanism and biological function of ATP13A2 have not been established. We found that loss of ATP13A2 function leads to accumulation of enlarged lysosomes, impaired lysosomal turnover of autophagic vesicles and impaired lysosomal degradation capacity. This lysosomal dysfunction results in preferential accumulation of α-synuclein and toxicity in neurons. Importantly, depletion of endogenous α-synuclein attenuated the toxicity in ATP13A2-deficient neurons, suggesting that loss of ATP13A2 mediates neurotoxicity at least partially via lysosomal dysfunction and consequent accumulation of α-synuclein. In addition, silencing of ATP13A2 in the Caenorhabditis elegans model of Parkinson disease has enhanced α-synuclein mediated degeneration of dopaminergic neurons, further underscoring the functional link between ATP13A2 and α-synuclein in neurodegeneration. Furthermore, in order to elucidate a normal biological function of ATP13A2 protein we identified its interacting partners that revealed putative role for ATP13A2 in vesicular trafficking and fusion. Importantly, a subset of these interactors was modifiers of α-synuclein aggregation and neurotoxicity in Caenorhabditis elegans, further supporting a functional link between ATP13A2 and α-synuclein.
Our findings implicate lysosomal dysfunction and α-synuclein accumulation in the pathogenesis of Kufor-Rakeb syndrome and suggest that upregulation of lysosomal function and downregulation of α-synuclein represent promising therapeutic strategies for this disorder.Lizosomi su važni za održavanje neuronske homeostaze kroz razgradnju oštećenih organela i nakupljenih proteina. Brojni dokazi ukazuju na postojanje lizosomske disfunkcije u nekoliko neurodegenerativnih bolesti, uključujući Parkinsonovu, Alzheimerovu i Huntingtonovu bolest. Nadalje, više od dvije-trećine lizosomskih bolesti odlaganja okarakterizirane su poremećajima središnjeg živčanog sustava, što pokazuje da su neuroni posebno osjetljivi na lizosomske nepravilnosti. Kako bi smo što detaljnije ispitali lizosomsku funkciju u neurodegeneraciji vrlo je značajno istražiti neurodegenerativne bolesti uzrokovane mutacijama u lizosomskim proteinima. Jedna od tih bolesti je i Kufor-Rakeb sindrom koji je uzrokovan mutacijama u lizosomskom proteinu ATP13A2/PARK9 i okarakteriziran kao juvenilni parkinsonizam s piramidalnom degeneracijom i demencijom. Prijašnja otkrića sugeriraju da ATP13A2 ima važnu ulogu u nepravilnom smatanju i toksičnosti α-sinukleina (proteina uključenog u Parkinsonovu bolest i slične sinukleinopatije), no biološka funkcija proteina ATP13A2 kao ni mehanizam povezanosti proteina ATP13A2 i α-sinukleina još nisu poznati. Našim istraživanjem otkrili smo da gubitak funkcije ATP13A2 dovodi do nakupljanja povećanih lizosoma, poremećene lizosomske razgradnje proteina i autofagosoma. Ova lizosomska disfunkcija rezultira nakupljanje α-sinukleina i smrću neurona. Ujedno, utišavanje endogenog α-sinukleina smanjilo je toksičnost u neuronima s utišanim ATP13A2 genom, što sugerira da je neurotoksičnost uzrokovana gubitkom ATP13A2 jednim dijelom posredovana disfunkcijom lizosoma i akumulacijom α-sinukleina. Osim toga, utišavanje ATP13A2 u Caenorhabditis elegans modelu za Parkinsonovu bolest pojačalo je α-sinuklein-posredovanu degeneraciju dopaminskih neurona, što dodatno upućuje na funkcionalnu povezanost između ATP13A2 i α-sinukleina u procesu nerodegeneracije. Nadalje, kako bismo rasvijetlili znanje o normalnoj biološkoj funkciji ATP13A2 proteina, identificirali smo njegove inter-reagirajuće partnere koji su pokazali da ATP13A2 igra ulogu u procesima prijenosa i stapanja vezikula. Značajno je spomenuti i da su pojedini interaktori povećali nakupljanje i neurotoksičnost α-sinukleina u Caenorhabditis elegans, što je pružilo daljne dokaze o funkcionalnoj povezanosti ATP13A2 i α-sinukleina.
Naša otkrića impliciraju lizosomsku disfunkciju i nakupljanje α-sinukleina kao važne elemente u patogenezi Kufor-Rakeb sindroma te ukazuju na to da pojačavanje funkcije lizosoma i smanjivanje razine α-sinukleina predstavljaju obećavajuće terapijske strategije za ovu bolest
Going Beyond Counting First Authors in Author Co-citation Analysis
No full textThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
No full text“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
No full textWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
No full textWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
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