Aging-dependent altered transcriptional programs underlie activity impairments in human C9orf72-mutant motor neurons

peer-reviewed
Erstveröffentlichung
2022-06-14Authors
Sommer, Daniel
Rajkumar, Sandeep
Schneider-Seidel, Kerstin Mira
Aly, Amr
Ludolph, Albert C.
Wissenschaftlicher Artikel
Published in
Frontiers in Molecular Neuroscience ; 10 (2022). - Art.-Nr. 3389. - eISSN 1662-5099
Link to original publication
https://dx.doi.org/10.3389/fnmol.2022.894230Faculties
Medizinische FakultätInstitutions
Institut für Anatomie und ZellbiologieUKU. Klinik für Neurologie
External cooperations
Deutsches Zentrum für Neurodegenerative Erkrankungen ( DZNE) UlmDocument version
published version (publisher's PDF)Abstract
Amyotrophic Lateral Sclerosis (ALS) is an incurable neurodegenerative disease
characterized by dysfunction and loss of upper and lower motor neurons (MN).
Despite several studies identifying drastic alterations affecting synaptic composition
and functionality in different experimental models, the specific contribution of impaired
activity to the neurodegenerative processes observed in ALS-related MN remains
controversial. In particular, contrasting lines of evidence have shown both hyper- as
well as hypoexcitability as driving pathomechanisms characterizing this specific neuronal
population. In this study, we combined high definition multielectrode array (HD-MEA)
techniques with transcriptomic analysis to longitudinally monitor and untangle the
activity-dependent alterations arising in human C9orf72-mutant MN. We found a timedependent
reduction of neuronal activity in ALSC9orf72 cultures occurring as synaptic
contacts undergo maturation and matched by a significant loss of mutant MN upon
aging. Notably, ALS-related neurons displayed reduced network synchronicity most
pronounced at later stages of culture, suggesting synaptic imbalance. In concordance
with the HD-MEA data, transcriptomic analysis revealed an early up-regulation of
synaptic terms in ALSC9orf72 MN, whose expression was decreased in aged cultures.
In addition, treatment of older mutant cells with Apamin, a KC channel blocker
previously shown to be neuroprotective in ALS, rescued the time-dependent loss of
firing properties observed in ALSC9orf72 MN as well as the expression of maturityrelated
synaptic genes. All in all, this study broadens the understanding of how
impaired synaptic activity contributes to MN degeneration in ALS by correlating
electrophysiological alterations to aging-dependent transcriptional programs.
DFG Project THU
SFB 1506 Teilprojekt A01 / Synaptische Alterung als “physiologische Synaptopathie“ / DFG / 450627322
Project uulm
Bausteinprogramm der Medizinischen Fakultät / Universität Ulm / L.SBN.0162
Promotionsprogramm Experimentelle Medizin / Medizinische Fakultät der Universität Ulm
Promotionsprogramm Experimentelle Medizin / Medizinische Fakultät der Universität Ulm
Publication funding
Open-Access-Förderung durch die Medizinische Fakultät der Universität Ulm
Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 491116205
Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 491116205
Is supplemented by
https://www.frontiersin.org/articles/10.3389/fnmol.2022.894230/full#supplementary-materialSubject headings
[GND]: Myatrophische Lateralsklerose | Motoneuron | Synapse[MeSH]: Amyotrophic lateral sclerosis | Motor neuron disease
[Free subject headings]: HiPSC | ALS (amyotrophic lateral sclerosis) | Motor neuron (MN) | Transcriptomic (RNA-Seq) | Neuronal excitability
[DDC subject group]: DDC 610 / Medicine & health
Metadata
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Please use this identifier to cite or link to this item: http://dx.doi.org/10.18725/OPARU-44641
Sommer, Daniel et al. (2022): Aging-dependent altered transcriptional programs underlie activity impairments in human C9orf72-mutant motor neurons. Open Access Repositorium der Universität Ulm und Technischen Hochschule Ulm. http://dx.doi.org/10.18725/OPARU-44641
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