The role of Serum Response Factor (SRF) in motoneuron vulnerability in Amyotrophic Lateral Sclerosis (ALS)
Loading...
Date
2024-03-28
Authors
Dikwella, Natalie
Journal Title
Journal ISSN
Volume Title
Publication Type
Dissertation
Published in
Abstract
Changes in neuronal activity modulate the vulnerability of motoneurons (MNs) in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). So far, the molecular basis of neuronal activity's impact in ALS is poorly understood. Herein, we investigated the impact of deleting the neuronal activity-stimulated transcription factor (TF) serum response factor (SRF) in MNs of SOD1G93A mice. SRF was present in vulnerable MMP9+ MNs. Ablation of SRF in MNs induced an earlier disease onset starting around 7-8 weeks after birth, as revealed by enhanced weight loss and decreased motor ability. This earlier disease onset in SRF-depleted MNs was accompanied by a mild elevation of neuroinflammation and neuromuscular synapse degeneration, whereas overall MN numbers and mortality were unaffected. In SRF-deficient mice, MNs showed impaired induction of autophagy-encoding genes, suggesting a potentially new SRF function in transcriptional regulation of autophagy. Complementary, constitutively active SRF-VP16 enhanced autophagy-encoding gene transcription and autophagy progression in cells. Furthermore, SRF-VP16 decreased ALS-associated aggregate induction. Chemogenetic modulation of neuronal activity uncovered SRF as having important TF-mediating activity-dependent effects, which might be beneficial to reduce ALS disease burden. Thus, our data identify SRF as a gene regulator connecting neuronal activity with the cellular autophagy program initiated in degenerating MNs.
Description
Faculties
Medizinische Fakultät
Institutions
UKU. Klinik für Neurologie
Institut für Neurobiochemie
Institut für Neurobiochemie
Citation
DFG Project uulm
EU Project THU
Other projects THU
License
CC BY 4.0 International
Is version of
Has version
Supplement to
Supplemented by
Has erratum
Erratum to
Has Part
Part of
DOI external
DOI external
Institutions
Periodical
Degree Program
DFG Project THU
item.page.thu.projectEU
item.page.thu.projectOther
Series
Keywords
ALS, SRF, Activity dependent transcription, In vivo, Myatrophische Lateralsklerose, Serum Response Factor, Autophagie <Physiologie>, Transkriptionsfaktor, Amyotrophic lateral sclerosis, Serum Response Factor, Autophagy, Transcription factors, Transcriptional activation, DDC 610 / Medicine & health