Research Group Simon

Our research interests are focused on understanding the synaptic and cellular mechanisms involved in neurodegenerative diseases, with emphasis on spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS). In particular, our group is interested in deciphering the correlation, or at times the disconnect, between neuronal death and neuronal dysfunction. We combine electrophysiology, whole tissue clearing, modern imaging, and molecular biology in mouse models of motor neuron diseases to study defects in motor circuits and their underlying mechanisms.

Mechanisms of motor unit pathology in SMA and ALS mice (DFG funded)

A motor unit consists of one motor neuron and all of the muscle fibers that it innervates. The motor unit serves as a bridge between the central and peripheral nervous system and commands movement by forming a specialized excitatory synapse between motor neuron and muscle fiber, the neuromuscular junction (NMJ). Degeneration of motor units is the hallmark of motor neuron diseases, causing muscle atrophy, paralysis and ultimately death of both SMA and ALS patients. Previously, we showed that inhibition of the p53 death pathway entirely prevents motor neuron death in SMA mice (Simon et al., 2017). However, these recued motor neurons still retract their axons from the NMJs at the muscle, implying that different mechanisms may be involved in motor neuron death and axonal pathology. Therefore, we now focus on NMJ pathology in ALS and SMA mice to understand the mechanisms of axonal retraction and its link to motor neuron dysfunction.Whole tissue clearing to visualize motor units in motor neuron diseases.
Motor axons (green) innervating postsynaptic parts of the NMJ (magenta) in cleared whole mount muscle of a wild type (A) and SMA (B) animal. L1-3=lumbar ventral roots 1-3. Scale bar=300µm. NMJs innervated by L1 motor neurons are marked with dotted boxes and magnified in A’ (wild type) and B’ (SMA). Note the retraction of the motor axons from denervated NMJs in B’ (magenta, without green). Scale bar=100µm. (C) L5 motor neurons back labeled by L5 ventral root fill with a fluorescent dye, subsequent whole spinal cord clearing and (C’) 3D reconstruction. Scale bar=60µm.

​Neuronal death and dysfunction in the cerebellum of ALS mice

In many neurodegenerative diseases, affected neurons become dysfunctional prior to their death. In these cases, dysfunction may be the trigger for neuronal death. To study this hypothesis, we focus on the cerebellum, in which functional and morphological changes have been detected in ALS patients. The cerebellum profoundly contributes to movement by processing sensory input to modulate spinal motor circuits. Functional impairment of the cerebellum might contribute to the impaired motor output of ALS patients. However, the mechanisms of death and dysfunction of cerebellar neurons are not well understood. To gain insight into these processes, we screen for neuronal death in cerebella of ALS mouse models in collaboration with Neil Shneider (Columbia University) using modern imaging approaches. To study functional changes in cerebellar neurons, we apply whole-cell patch-clamp recordings in a tight collaboration with Stefan Hallermann to correlate dysfunction with neuronal death in ALS in vivo. Ultimately, we plan to interfere with this disease process to test whether improving dysfunction might prevent cell death, or vice versa.Morphological and functional characterization of cerebellar Purkinje cells.
(A) Distribution of Purkinje cells in an adult murine cerebellum. Scale bar=400µm. (B) Magnification of a small area of a cerebellar lobules reveals detailed Purkinje cells morphology. Scale bar=40 µm. (C) Spontaneous action potential firing at resting potential of a Purkinje cell using whole-cell patch clamp recording. Scale bar=20mV/50ms.​

• Doctoral theses for medical students
• Bachelor and Master theses for biology and biochemistry students​

Kong L., Hassinan, C., Gerstner, F., Buettner, J.M., Petigrow, J., Valdivia, D., Chan-Cortés, M., Mistri, A., Cao, A., McGaugh, S.A., Denton, M., Brown, S., Ross, J., Schwab, M., Simon, C.M., Sumner, C. (2023).
Boosting neuregulin 1 type-III expression hastens SMA motor axon maturation
Acta neuropathol commun (accepted)

Hennlein, L., Ghanawi, H., Gerstner, F., Palominos Garcia, E., Yildirim, E., Saal-Bauernschubert, L., Moradi, M., Deng, C., Klein, T., Appenzeller, S., Sauer, M., Briese, M., Simon, C.M., Sendtner, M., Jablonka, S. (2023).
Plastin 3 rescues cell surface translocation and activation of TrkB in spinal muscular atrophy.
J Cell Biol 222. 10.1083/jcb.202204113.

Buettner, J.M., Sowoidnich, L., Gerstner, F., Blanco-Redondo, B., Hallermann, S., Simon, C.M. (2022).
p53-dependent c-Fos expression is a marker but not executor for motor neuron death in spinal muscular atrophy mouse models.
Front. Cell. Neurosci., doi.org/10.3389/fncel.2022.103

Tisdale, S., Van Alstyne, M., Simon, C.M., Mentis, G.Z., and Pellizzoni, L. (2022).
SMN controls neuromuscular junction integrity through U7 snRNP.
Cell Rep 40, 111393. 10.1016/j.celrep.2022.111393.

Buettner, J.M., Kirmann, T., Mentis, G.Z., Hallermann, S., and Simon, C.M. (2022).
Laser microscopy acquisition and analysis of premotor synapses in the murine spinal
cord.
STAR Protoc 3, 101236. 10.1016/j.xpro.2022.101236.

Buettner, J.M., Sime Longang, J.K., Gerstner, F., Apel, K.S., Blanco-Redondo, B., Sowoidnich, L., Janzen, E., Langenhan, T., Wirth, B., and Simon, C.M. (2021).
Central synaptopathy is the most conserved feature of motor circuit pathology across spinal muscular atrophy mouse models.
iScience 24, 103376. 10.1016/j.isci.2021.103376.

Kong, L., Valdivia, D.O., Simon, C.M., Hassinan, C., Delestree, N., Ramos, D., Park J.H., Celeste, P., Xu X., Crowder, M., Gyrzb, C., King, Z., Petrillo, M., Swoboda, K., Davis, C., Lutz, C., Weetall, M., Naryshkin, N., Crawford, T.O., Mentis, G.Z., Sumner, C.J. (2021).
​Impaired prenatal motor axon development necessitates early therapeutic intervention ​in severe SMA.
Sci. Transl. Med. 13, eabb6871

Simon, C.M*., Blanco-Redondo, B., Buettner, J.M., Pagiazitis, J.G., Fletcher, E.V., Sime Longang, J.K., and Mentis, G.Z. (2021).
Chronic Pharmacological Increase of Neuronal Activity Improves Sensory-Motor Dysfunction in Spinal Muscular Atrophy Mice.
J Neurosci 41, 376-389, *Correspondence

Simon, C.M., Van Alstyne, M., Lotti, F., Bianchetti, E., Tisdale, S., Watterson, D.M., Mentis, G.Z., and Pellizzoni, L. (2019).
Stasimon Contributes to the Loss of Sensory Synapses and Motor Neuron Death in a Mouse Model of Spinal Muscular Atrophy.
Cell Rep 29, 3885-3901 e3885.

Van Alstyne M, Simon CM, Sardi SP, Shihabuddin LS, Mentis GZ, Pellizzoni L. (2018)
Dysregulation of Mdm2 and Mdm4 alternative splicing underlies motor neuron death in spinal muscular atrophy.
Genes Dev. Aug 1;32(15-16):1045-1059

Simon CM, Dai Y, Van Alstyne M, Koutsioumpa C, Pagiazitis JG, Chalif JI, Wang X, Rabinowitz JE, Pellizzoni L, Henderson CE, Mentis GZ (2017)
Converging mechanisms of p53 activation drive motor neuron degeneration in spinal muscular atrophy.
Cell Reports 21, 3767–3780

Fletcher EV, Simon, CM, Pagiazitis, JG, Chalif, JI, Vukojicic, A, Drobac, E, Wang, X, and Mentis, GZ (2017)
Reduced sensory synaptic excitation impairs motor neuron function via Kv2.1 in spinal muscular atrophy.
Nature neuroscience 20, 905-916

Simon CM, Janas A.M, Lotti F, Tabia JC, Pellizzoni L, Mentis GZ (2016)
A stem cell model of the motor circuit uncouples motor neuron death from hyperexcitability induced by SMN deficiency.
Cell Reports 16, 1416–1430

Jesse CM, Bushuven E, Tripathi P, Chandrasekar A, Simon CM, Drepper C, Yamoah A, Dreser A, Katona I, Johann S, Beyer C, Wagner S, Grond M, Nikolin S, Anink J, Troost D, Sendtner M, Goswami A, Weis J (2016)
ALS-associated endoplasmic reticulum proteins in denervated skeletal muscle: Implications for motor neuron disease pathology.
Brain Pathology doi: 10.1111/bpa.12453

Mendelsohn AI, Simon CM, Abbott LF, Mentis GZ, Jessell T (2015)
Activity Regulates the Incidence of Heteronymous Sensory-Motor Connections.
Neuron Jul 1;87(1):111-23

Simon CM, Gunnersen JM, Rauskolb S, Holtmann B, Drepper C, Braga M, Wiese S, Jablonka S, Puehringer D, Dombert B, Zielasek J, Hoeflich A, Silani V, Wolf E, Kneitz S, Sommer C, Toyka K, Sendtner M (2015)
Dysregulated IGFBP5 expression causes axon degeneration and motoneuron loss in diabetic neuropathy.
Acta Neuropathol. 10.1007/s00401-015-1446-8

de Nooij JC, Simon CM, Simon A, Doobar S, Steel KP, Banks RW, Mentis GZ, Bewick GS, Jessell T (2015)
The PDZ-domain protein Whirlin facilitates mechanosensory signaling in mammalian
proprioceptors.
J Neurosci. 35(7):3073-84

Dombert B, Sivadasan R, Simon CM, Jablonka S, Sendtner M (2014)
Presynaptic localization of Smn and hnRNP R in axon terminals of embryonic and postnatal mouse motoneurons.
PLoS One, 10; 9(10):e110846

Simon CM, Jablonka, S, Ruiz, R, Tabares, L, Sendtner, M (2010)
Ciliary neurotrophic factor-induced sprouting preserves motor function in a mouse model of spinal muscular atrophy.
Hum. Mol. Genet., 19 973-986

Fischer, M, Pereira, PM, Holtmann, B, Simon, CM, Hanauer, A, Heisenberg, M, Sendtner, M (2009)
P90 ribosomal s6 kinase 2 negatively regulates axon growth in motoneurons.
Mol. Cell Neurosci., 42 134-141

Christian Simon, PhD
Carl-Ludwig-Institute for Physiology Leipzig University,
Liebigstr. 27, 04103 Leipzig, Germany
Room E105
phone: +49 (0) 341 97 15325
email: Christian.Simon@medizin.uni-leipzig.de​