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 6

Reduced autophagy induction upon SRF deletion in SOD1 mice.

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Reduced autophagy induction upon SRF deletion in SOD1 mice. (A) MNs from...
(A) MNs from the ventral horn of P50 mice were subjected to qPCR analysis. Arrows point at MNs before dissection. After dissection, MNs were selectively removed. The mRNA abundance of human Sod1 was specifically increased in MNs of mSOD1 and mSOD1/Srf-KO mice. (B) Srf mRNA was removed from MNs of Srf-KO and mSOD1/Srf-KO animals. (C–E) cFos (C), Egr1 (D), and Npas4 (E) were reduced in Srf-KO animals and to a similar extent in mSOD1/Srf-KO mice. (F–I) In relation to WT, mRNA levels of Atg101 (F), Atg9a (G), Atg10 (H), and Atg14 (I) were reduced in Srf-KO and mSOD1 MNs. It is important to note that, in mSOD1/Srf KO MNs, the mRNA levels of all 4 genes were lower compared with mSOD1 MNs. (J–L) mRNA abundance of Map1lc3a (J), Beclin1 (K), and Atg7 (L) was reduced in Srf-KO and upregulated in mSOD1 MNs in relation to WT. The upregulation of all 3 genes in mSOD1 MNs was not observed in mSOD1/Srf-KO MNs. (M) p62 mRNA was not induced in Srf-KO and mSOD1/Srf-KO MNs in relation to WT and mSOD1 MNs. (N) Lamp5 abundance was downregulated in Srf-KO, mSOD1 and mSOD1/Srf-KO MNs in comparison with WT. (O and P) Ulk1 (O) and Fip200 (P) abundance was not overtly changed between cohorts. In A–P, n values are indicated by each colored dot reflecting 1 mouse. *, #, § denote significance in relation to WT, Srf-KO, and mSOD1, respectively. *P < 0.05, **P < 0.01, ***P < 0.001. Statistical testing was performed by 1-way ANOVA with Tukey corrections. Scale bar: 30 μm.