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 3

SRF deletion results in earlier motor impairments in SOD1 mice.

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SRF deletion results in earlier motor impairments in SOD1 mice. (A and B...
(A and B) Male (A) and female (B) mSOD1/Srf-KO mice dropped down earlier in the inverted grid test compared with mSOD1 mice. WT and Srf-KO mice held on for 180 seconds. (C and D) In the pole test, male (C) and female (D) mSOD1/Srf-KO mice could not climb down the pole as quickly as mSOD1 mice. In contrast, WT and Srf-KO mice climbed down within 10 seconds. These data are presented as mean ± SEM. (E and F) The survival of male (E) or female (F) mSOD1/Srf-KO mice was comparable with mSOD1 mice. (G and H) The disease onset calculated on the basis of the body weight curves was earlier in male mSOD1/Srf-KO mice compared with mSOD1 mice (G). In female mice, the same tendency was observed (H). In A–D, each colored dot represents 1 mouse. n values are indicated in A and B. Statistical testing was performed by 2-way ANOVA with Tukey corrections (A–D) and Mantel-Cox test (E–H). **P < 0.01, ***P < 0.001.