SMN deficiency disrupts brain development in a mouse model of severe spinal muscular atrophy

Abstract

Reduced expression of the survival motor neuron (SMN) gene causes the childhood motor neuron disease spinal muscular atrophy (SMA). Low levels of ubiquitously expressed SMN protein result in the degeneration of lower motor neurons, but it remains unclear whether other regions of the nervous system are also affected. Here we show that reduced levels of SMN lead to impaired perinatal brain development in a mouse model of severe SMA. Regionally selective changes in brain morphology were apparent in areas normally associated with higher SMN levels in the healthy postnatal brain, including the hippocampus, and were associated with decreased cell density, reduced cell proliferation and impaired hippocampal neurogenesis. A comparative proteomics analysis of the hippocampus from SMA and wild-type littermate mice revealed widespread modifications in expression levels of proteins regulating cellular proliferation, migration and development when SMN levels were reduced. This study reveals novel roles for SMN protein in brain development and maintenance and provides the first insights into cellular and molecular pathways disrupted in the brain in a severe form of SMA.

Dysregulation of ubiquitin homeostasis and β-catenin signaling promote spinal muscular atrophy

“…In order to examine neuronal material that was biologically relevant and yet free from contamination by nuclear and/or myelin proteins (the abundance of which can hamper the sensitivity of proteomics screens), we initially performed unbiased iTRAQ comparative proteomics on synapses isolated from the hippocampus of presymptomatic (P1) "severe" SMA mice (Smn -/-SMN2 tg/tg ) compared with littermate controls (Smn +/+ SMN2 tg/tg ). We chose to use hippocampal synaptosomes for these experiments due to the known susceptibility of the hippocampus in mouse models of SMA (11), as well as the known susceptibility of synaptic compartments of neurons in SMA during the early stages of disease (7,8). Biochemical analysis of isolated synaptic preparations from mice confirmed the presence of SMN protein and its known interacting proteins (e.g., gemin5) in the synaptic cytoplasm at CNS synapses ( Supplemental Figures 1 and 2; supplemental material available online with this article; doi:10.1172/JCI71318DS1).…”

Motor neuron cell-nonautonomous rescue of spinal muscular atrophy phenotypes in mild and severe transgenic mouse models

“…In the central nervous system (CNS), impaired neuritogenesis and neurogenesis in the hippocampus and retina have been observed (Wishart et al 2010;Liu et al 2011). In the peripheral nervous system (PNS), loss of Schwann cells and sensory neuropathy have been documented (Rudnik-Schoneborn et al 2003;Murray et al 2012;Yonekawa et al 2013).…”

Decreasing Disease Severity in Symptomatic,Smn−/−;SMN2+/+, Spinal Muscular Atrophy Mice Following scAAV9-SMN Delivery

“…These mice are born symptomatic, gain minimal body weight, and live approximately 4-6 days. Recently, this model has been shown to exhibit nonneuronal defects, including cardiac dysfunction and disrupted hippocampal development (Shababi et al, 2010b;Wishart et al, 2010). Due to the severity of the model, improving its phenotype via therapeutics has proven to be difficult.…”