SRF deletion results in earlier disease onset in a mouse model of amyotrophic lateral sclerosis
Jialei Song, Natalie Dikwella, Daniela Sinske, Francesco Roselli, Bernd Knöll
Jialei Song, Natalie Dikwella, Daniela Sinske, Francesco Roselli, Bernd Knöll
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Research Article Neuroscience

SRF deletion results in earlier disease onset in a mouse model of amyotrophic lateral sclerosis

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.

Authors

Jialei Song, Natalie Dikwella, Daniela Sinske, Francesco Roselli, Bernd Knöll

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Figure 1

SRF is present in vulnerable MNs.

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SRF is present in vulnerable MNs. (A–D) Ventral horns from P50 (A and B)...
(A–D) Ventral horns from P50 (A and B) or P90 (C and D) WT (A and C) or mSOD1 (B and D) mice were stained for ChAT (blue), MMP9 (red), and SRF (green). SRF was present in nonvulnerable MMP9– and vulnerable MMP9+ MNs in WT and mSOD1 mice. (E and F) In Srf KO MNs (F), SRF was absent from VAChT+ MNs at P90 in contrast to WT MNs (E). (G) In WT and mSOD1 mice, approximately 50% of MNs were SRF+ at P50. At P90, abundance of SRF+ MNs was decreased in mSOD1 mice. There was no significant change in WT MNs between P50 and P90. (H) In WT mice, SRF was more present in MMP9+ MNs (~60%) compared with MMP9– MNs (~40%). In mSOD1 mice, SRF was significantly more present in vulnerable MMP9+ MNs compared with MMP9– MNs at P50, in contrast to P90. (I) SRF was nearly absent from MNs in Srf-KO and SOD1/Srf-KO mice compared with WT and SOD1 animals at P90. In G–I, each dot represents 1 mouse. (G and H) n = 486 MNs (WT, P50), 377 MNs (mSOD1, P50); 512 MNs (WT, P90), 411 MNs (mSOD1, P90). (I) n = 598 MNs (WT), 558 MNs (Srf KO), 584 MNs (mSOD1), and 650 MNs (mSOD1/Srf KO). Statistical testing was performed by 1-way ANOVA with Tukey corrections. Scale bar: 30 μm (A–F). *P < 0.05, **P < 0.01, ***P < 0.001.