Dynamics of survival of motor neuron (SMN) protein interaction with the mRNA‐binding protein IMP1 facilitates its trafficking into motor neuron axons

Abstract

Spinal muscular atrophy (SMA) is a lethal neurodegenerative disease specifically affecting spinal motor neurons. SMA is caused by the homozygous deletion or mutation of the survival of motor neuron 1 (SMN1) gene. The SMN protein plays an essential role in the assembly of spliceosomal ribonucleoproteins. However, it is still unclear how low levels of the ubiquitously expressed SMN protein lead to the selective degeneration of motor neurons. An additional role for SMN in the regulation of the axonal transport of mRNA-binding proteins (mRBPs) and their target mRNAs has been proposed. Indeed, several mRBPs have been shown to interact with SMN, and the axonal levels of few mRNAs, such as the β-actin mRNA, are reduced in SMA motor neurons. In this study we have identified the β-actin mRNA-binding protein IMP1/ZBP1 as a novel SMN-interacting protein. Using a combination of biochemical assays and quantitative imaging techniques in primary motor neurons, we show that IMP1 associates with SMN in individual granules that are actively transported in motor neuron axons. Furthermore, we demonstrate that IMP1 axonal localization depends on SMN levels, and that SMN deficiency in SMA motor neurons leads to a dramatic reduction of IMP1 protein levels. In contrast, no difference in IMP1 protein levels was detected in whole brain lysates from SMA mice, further suggesting neuron specific roles of SMN in IMP1 expression and localization. Taken together, our data support a role for SMN in the regulation of mRNA localization and axonal transport through its interaction with mRBPs such as IMP1.

SMN affects membrane remodelling and anchoring of the protein synthesis machinery

“…However, an emerging idea is that the loss of additional function(s) of SMN unrelated to RNA splicing could co-contribute to SMA pathogenesis. In particular, it has been strongly suggested that SMN is involved in the trafficking and/or translation of target transcripts (Rossoll et al, 2003;Tadesse et al, 2008;Glinka et al, 2010;Peter et al, 2011;Hubers et al, 2011;Fallini et al, 2011Fallini et al, , 2014Yamazaki et al, 2012;Rathod et al, 2012;Sanchez et al, 2013). In this context, it is noteworthy to mention cross-species conserved genes able to mitigate the SMN loss-of-function defects (Dimitriadi et al, 2010).…”

Subcellular transcriptome alterations in a cell culture model of spinal muscular atrophy point to widespread defects in axonal growth and presynaptic differentiation

“…Further hypotheses on the etiology of SMA have emerged by (i) the observation that the SMN protein is localized in axons of motoneurons (Zhang et al 2003) and (ii) the identification of a number of RNA-binding proteins interacting with SMN such as hnRNP R and Q (Rossoll et al 2002), FMRP (Piazzon et al 2008), HuD (Fallini et al 2011), IMP1 (Fallini et al 2013) as well as TDP-43 (Wang et al 2002;Tsuiji et al 2013), and FUS (Yamazaki et al 2012). The latter two are implicated in ALS.…”

SMN-targeted therapeutics for spinal muscular atrophy: are we SMArt enough yet?

“…If there is a universal requirement for SMN, why are motor neurons selectively affected by its loss, and where does SMA first manifest? Does SMN dysfunction begin at the level of the motor neuron cell body, the axon, or the NMJ (11,12), and what effect does reduced SMN have on other components of the neuromuscular circuitry (13)?…”