NSC Physiological Features in Spinal Muscular Atrophy: SMN Deficiency Effects on Neurogenesis

Abstract

While the U.S. Food and Drug Administration and the European Medicines Evaluation Agency have recently approved new drugs to treat spinal muscular atrophy 1 (SMA1) in young patients, they are mostly ineffective in older patients since many motor neurons have already been lost. Therefore, understanding nervous system (NS) physiology in SMA patients is essential. Consequently, studying neural stem cells (NSCs) from SMA patients is of significant interest in searching for new treatment targets that will enable researchers to identify new pharmacological approaches. However, studying NSCs in these patients is challenging since their isolation damages the NS, making it impossible with living patients. Nevertheless, it is possible to study NSCs from animal models or create them by differentiating induced pluripotent stem cells obtained from SMA patient peripheral tissues. On the other hand, therapeutic interventions such as NSCs transplantation could ameliorate SMA condition. This review summarizes current knowledge on the physiological properties of NSCs from animals and human cellular models with an SMA background converging on the molecular and neuronal circuit formation alterations of SMA fetuses and is not focused on the treatment of SMA. By understanding how SMA alters NSC physiology, we can identify new and promising interventions that could help support affected patients.

Keywords: differentiation; epigenetic; induced pluripotent stem cells; mitochondria; spinal muscular atrophy; survival motor neuron.

Figure 1

Schematic representation of methylation levels in the survival of motor neuron 2 (SMN2) gene at various differentiation stages during motor neuron (MN) development: induced pluripotent stem cells (iPSCs), neuroepithelial precursors (NEP) in panel (A), immature MNs (IMN), and mature MNs (MMNs) in panel (B). Green represents healthy individuals, blue represents SMA2 patients, and red represents SMA1 patients. The scheme also describes methylation in the SMN2 gene’s four different CpG islands.

Figure 2

Scheme describing altered interactions in spinal muscular atrophy (SMA) cells during MN development. Each cell drawing is divided in two: the green-shaded half represents cells from healthy individuals, while the orange-shaded half represents cells from SMA patients. Reduced SMA2 methylation is accompanied by an increase in the methylation of various genes. The low SMN protein level alters different pathways and changes protein interactions either at the soma or neurite level. SMA patient mitochondria do not interact properly with the endoplasmic reticulum and have an inappropriate morphology. (A): iPSCs; (B): NEPs; (C): IMNs; and (D): MMNs. OCT4: POU class 5 homeobox 1; LYST: lysosomal trafficking regulator; PAX6: paired box 6; HB9: motor neuron and pancreas homeobox 1 gene; and CHAT: Choline acetyltransferase.