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000271071 1001_ $$aLehmann, Johannes$$b0
000271071 245__ $$aHeterozygous knockout of Synaptotagmin13 phenocopies ALS features and TP53 activation in human motor neurons.
000271071 260__ $$aLondon [u.a.]$$bNature Publishing Group$$c2024
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000271071 520__ $$aSpinal motor neurons (MNs) represent a highly vulnerable cellular population, which is affected in fatal neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). In this study, we show that the heterozygous loss of SYT13 is sufficient to trigger a neurodegenerative phenotype resembling those observed in ALS and SMA. SYT13+/- hiPSC-derived MNs displayed a progressive manifestation of typical neurodegenerative hallmarks such as loss of synaptic contacts and accumulation of aberrant aggregates. Moreover, analysis of the SYT13+/- transcriptome revealed a significant impairment in biological mechanisms involved in motoneuron specification and spinal cord differentiation. This transcriptional portrait also strikingly correlated with ALS signatures, displaying a significant convergence toward the expression of pro-apoptotic and pro-inflammatory genes, which are controlled by the transcription factor TP53. Our data show for the first time that the heterozygous loss of a single member of the synaptotagmin family, SYT13, is sufficient to trigger a series of abnormal alterations leading to MN sufferance, thus revealing novel insights into the selective vulnerability of this cell population.
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000271071 650_7 $$2NLM Chemicals$$aTumor Suppressor Protein p53
000271071 650_7 $$0134193-27-4$$2NLM Chemicals$$aSynaptotagmins
000271071 650_7 $$2NLM Chemicals$$aTP53 protein, human
000271071 650_2 $$2MeSH$$aHumans
000271071 650_2 $$2MeSH$$aTumor Suppressor Protein p53: metabolism
000271071 650_2 $$2MeSH$$aTumor Suppressor Protein p53: genetics
000271071 650_2 $$2MeSH$$aMotor Neurons: metabolism
000271071 650_2 $$2MeSH$$aMotor Neurons: pathology
000271071 650_2 $$2MeSH$$aSynaptotagmins: metabolism
000271071 650_2 $$2MeSH$$aSynaptotagmins: genetics
000271071 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: genetics
000271071 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: metabolism
000271071 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: pathology
000271071 650_2 $$2MeSH$$aHeterozygote
000271071 650_2 $$2MeSH$$aPhenotype
000271071 650_2 $$2MeSH$$aInduced Pluripotent Stem Cells: metabolism
000271071 650_2 $$2MeSH$$aInduced Pluripotent Stem Cells: pathology
000271071 650_2 $$2MeSH$$aCell Differentiation: genetics
000271071 650_2 $$2MeSH$$aGene Knockout Techniques
000271071 7001_ $$aAly, Amr$$b1
000271071 7001_ $$aSteffke, Christina$$b2
000271071 7001_ $$aFabbio, Luca$$b3
000271071 7001_ $$0P:(DE-2719)9003146$$aMayer, Valentin$$b4$$udzne
000271071 7001_ $$aDikwella, Natalie$$b5
000271071 7001_ $$0P:(DE-2719)9001676$$aHalablab, Kareen$$b6$$udzne
000271071 7001_ $$0P:(DE-2719)2812851$$aRoselli, Francesco$$b7
000271071 7001_ $$aSeiffert, Simone$$b8
000271071 7001_ $$0P:(DE-2719)2812855$$aBoeckers, Tobias M$$b9$$udzne
000271071 7001_ $$0P:(DE-2719)9002137$$aBrenner, David$$b10$$udzne
000271071 7001_ $$aKabashi, Edor$$b11
000271071 7001_ $$aMulaw, Medhanie$$b12
000271071 7001_ $$00000-0003-1496-4436$$aHo, Ritchie$$b13
000271071 7001_ $$0P:(DE-2719)9001873$$aCatanese, Alberto$$b14$$eLast author
000271071 773__ $$0PERI:(DE-600)2541626-1$$a10.1038/s41419-024-06957-3$$gVol. 15, no. 8, p. 560$$n8$$p560$$tCell death & disease$$v15$$x2041-4889$$y2024
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