Serum Response Factor (SRF) regulates motoneuron vulnerability and activity- dependent neuroprotection in Amyotrophic Lateral Sclerosis.
Final Report Abstract
The present project aimed at demonstrating the role of activity-induced neuroprotection in shaping the vulnerability of motoneurons in Amyotrophic Lateral Sclerosis (ALS). The program originated from the joint expertise of the two groups in motoneuron degeneration (Roselli) and activity-induced transcriptional regulation (Knöll). In particular, the transcription factor SRF (serum response factor) was taken into consideration, because of its prominence in inducing immediate-early genes and its tractable experimental conditions (its deletion is not lethal to the cells). The project was performed using a conditional mouse model for the deletion of SRF only in motoneurons in the context of the SOD1(G93A) mouse model, viral methods to use chemogenetics to induce neuronal firing and cellbased approaches to show the broad applicability of the identified mechanisms. It was shown that SRF deletion in MN makes the motoneurons more sensitive to ALS pathobiochemistry, accelerating disease onset by interfering with autophagy induction. Furthermore, loss of SRF in motoneurons prevented the beneficial effects of chemogenetically-driven excitation and simulated the consequences of activity suppression. We explored the effect of SRF gain of function on multiple ALS-related mutations in cellular models, demonstrating the stimulated autophagy clearance under SRF control. We further investigated SRF pathology in human ALS samples, showing the loss of SRF immunoreactivity and the formation of possible SRF aggregates in vulnerable MN.
Publications
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Diversity of Mammalian Motoneurons and Motor Units. Advances in Neurobiology, 131-150. Springer International Publishing.
Bączyk, Marcin; Manuel, Marin; Roselli, Francesco & Zytnicki, Daniel
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From Physiological Properties to Selective Vulnerability of Motor Units in Amyotrophic Lateral Sclerosis. Vertebrate Motoneurons, 375–394.
Bączyk, Marcin; Manuel, Marin; Roselli, Francesco & Zytnicki, Daniel
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SRF deletion results in earlier disease onset in a mouse model of amyotrophic lateral sclerosis. JCI Insight, 8(15).
Song, Jialei; Dikwella, Natalie; Sinske, Daniela; Roselli, Francesco & Knöll, Bernd
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A Roadmap of Peptide‐Based Materials in Neural Regeneration. Advanced Healthcare Materials, 14(2).
Tsai, Yu‐Liang; Song, Jialei; Shi, Rachel; Knöll, Bernd & Synatschke, Christopher V.
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Heterozygous knockout of Synaptotagmin13 phenocopies ALS features and TP53 activation in human motor neurons. Cell Death & Disease, 15(8).
Lehmann, Johannes; Aly, Amr; Steffke, Christina; Fabbio, Luca; Mayer, Valentin; Dikwella, Natalie; Halablab, Kareen; Roselli, Francesco; Seiffert, Simone; Boeckers, Tobias M.; Brenner, David; Kabashi, Edor; Mulaw, Medhanie; Ho, Ritchie & Catanese, Alberto
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Nerve injury converts Schwann cells in a long-term repair-like state in human neuroma tissue. Experimental Neurology, 382, 114981.
Deininger, Stefanie; Schumacher, Jakob; Blechschmidt, Anna; Song, Jialei; Klugmann, Claudia; Antoniadis, Gregor; Pedro, Maria; Knöll, Bernd & Meyer zu Reckendorf, Sofia
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Spinal motoneuron excitability is homeostatically-regulated through β-adrenergic neuromodulation in wild-type and presymptomatic SOD1 mice. openRxiv.
Antonucci, Stefano; Caron, Guillaume; Dikwella, Natalie; Krishnamurty, Sruthi Sankari; Harster, Anthony; Zarrin, Hina; Tahanis, Aboud; Heuvel, Florian olde; Danner, Simon M.; Ludolph, Albert C.; Grycz, Kamil; Bączyk, Marcin; Zytnicki, Daniel & Roselli, Francesco
