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 4

SRF deletion enhances microgliosis and accelerates neuromuscular junction denervation.

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SRF deletion enhances microgliosis and accelerates neuromuscular junctio...
(A–D) Ventral horns from P50 WT (A), Srf-KO (B), mSOD1 (C), and mSOD1/Srf-KO (D) mice were stained for VAChT (blue), microglia (IBA1; red), and astrocytes (GFAP; green). In mSOD1/Srf-KO mice, microglia and less pronounced astrocyte abundance was elevated compared with other cohorts (see M and N). (E–H) The MN number in ventral horns labeled with VAChT was reduced in mSOD1 (G) and mSOD1/Srf-KO (H) compared with WT (E) and Srf-KO (F) mice. However, no differences between mSOD1 (G) and mSOD1/Srf-KO (H) cohorts were discernible. (I–L) In mSOD1/Srf-KO mice (L), a reduction in NMJ innervation was observed (see NMJs marked with arrows). (M and N) Quantification of GFAP (M) and IBA1 (N) abundance in P50 and P90 mice. (O) The MN number was reduced in mSOD1 and mSOD1/Srf-KO cohorts at P50 and more pronounced at P90 compared with WT and Srf-KO mice. (P) In mSOD1/Srf-KO mice, the percentage of innervated NMJs was decreased significantly at P50 and with the same tendency at P90 in relation to mSOD1 mice. In M–P, each colored dot represents 1 mouse. In O, n of MNs/sections analyzed were for P50 as follows: 1,483/44 (WT); 1,713/51 (Srf KO); 1,484/50 (mSOD1); 1,428/50 (mSOD1/Srf KO). For P90: 1,322/40 (WT); 1330/40 (Srf KO); 988/40 (mSOD1); 940/41 (mSOD1/Srf KO). In P, n for NMJ were for P50 as follows: 462 (WT), 432 (Srf KO), 472 (mSOD1), 834 (mSOD1/Srf KO). n for NMJ were for P90 as follows: 456 (WT), 458 (Srf KO), 480 (mSOD1), 441 (mSOD1/Srf KO). Statistical testing was performed by 1-way ANOVA with Tukey corrections. Scale bar: 30 μm. *P < 0.05, **P < 0.01, ***P < 0.001.