TY  - JOUR
AU  - Lehmann, Johannes
AU  - Aly, Amr
AU  - Steffke, Christina
AU  - Fabbio, Luca
AU  - Mayer, Valentin
AU  - Dikwella, Natalie
AU  - Halablab, Kareen
AU  - Roselli, Francesco
AU  - Seiffert, Simone
AU  - Boeckers, Tobias M
AU  - Brenner, David
AU  - Kabashi, Edor
AU  - Mulaw, Medhanie
AU  - Ho, Ritchie
AU  - Catanese, Alberto
TI  - Heterozygous knockout of Synaptotagmin13 phenocopies ALS features and TP53 activation in human motor neurons.
JO  - Cell death & disease
VL  - 15
IS  - 8
SN  - 2041-4889
CY  - London [u.a.]
PB  - Nature Publishing Group
M1  - DZNE-2024-00943
SP  - 560
PY  - 2024
AB  - Spinal 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.
KW  - Humans
KW  - Tumor Suppressor Protein p53: metabolism
KW  - Tumor Suppressor Protein p53: genetics
KW  - Motor Neurons: metabolism
KW  - Motor Neurons: pathology
KW  - Synaptotagmins: metabolism
KW  - Synaptotagmins: genetics
KW  - Amyotrophic Lateral Sclerosis: genetics
KW  - Amyotrophic Lateral Sclerosis: metabolism
KW  - Amyotrophic Lateral Sclerosis: pathology
KW  - Heterozygote
KW  - Phenotype
KW  - Induced Pluripotent Stem Cells: metabolism
KW  - Induced Pluripotent Stem Cells: pathology
KW  - Cell Differentiation: genetics
KW  - Gene Knockout Techniques
KW  - Tumor Suppressor Protein p53 (NLM Chemicals)
KW  - Synaptotagmins (NLM Chemicals)
KW  - TP53 protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39097602
C2  - pmc:PMC11297993
DO  - DOI:10.1038/s41419-024-06957-3
UR  - https://pub.dzne.de/record/271071
ER  -