Quantcast


CURATOR
A pinboard by
Mia Huang

Postdoctoral Scholar, University of California San Diego

PINBOARD SUMMARY

Chemically synthesized glycomaterials that recapitulate the functions of native glycans

Glycans are important constituents that decorate the eukaryotic cell surface. Due to their chemical complexity, however, glycans are less studied compared to their protein counterparts. Here, we present a chemical strategy to mimic the natural macromolecular architecture of a class of glycans, termed glycosaminoglycans, in order to study their role in the developing neuromuscular junction. Our strategy presents an elegant solution towards the synthesis of chemically-defined homogeneous glycosaminoglycan conjugates, while obviating laborious synthetic procedures. Using these materials, we successfully recapitulated the functions of native muscle glycosaminoglycans. Furthermore, we discovered a differing role for soluble versus cell-surface anchored glycosaminoglycans in regulating the neuromuscular synapse.

3 ITEMS PINNED

Motor neuronal repletion of the NMJ organizer, Agrin, modulates the severity of the spinal muscular atrophy disease phenotype in model mice.

Abstract: Spinal muscular atrophy (SMA) is a common and often fatal neuromuscular disorder caused by low levels of the Survival Motor Neuron (SMN) protein. Amongst the earliest detectable consequences of SMN deficiency are profound defects of the neuromuscular junctions (NMJs). In model mice these synapses appear disorganized, fail to mature and are characterized by poorly arborized nerve terminals. Given one role of the SMN protein in orchestrating the assembly of spliceosomal snRNP particles and subsequently regulating the alternative splicing of pre-mRNAs, a plausible link between SMN function and the distal neuromuscular SMA phenotype is an incorrectly spliced transcript or transcripts involved in establishing or maintaining NMJ structure. In this study we explore the effects of one such transcript - Z+ Agrin - known to be a critical organizer of the NMJ. We confirm that low SMN protein reduces motor neuronal levels of Z+Agrin. Repletion of this isoform of Agrin in the motor neurons of SMA model mice increases muscle fiber size, enhances the post-synaptic NMJ area, reduces the abnormal accumulation of intermediate filaments in nerve terminals of the neuromuscular synapse and improves the innervation of muscles. While these effects are independent of changes in SMN levels or increases in motor neuron numbers they nevertheless have a significant effect on the overall disease phenotype, enhancing mean survival in severely affected SMA model mice by ∼40%. We conclude that Agrin is an important target of the SMN protein and that mitigating NMJ defects may be one strategy in treating human spinal muscular atrophy.

Pub.: 06 Apr '17, Pinned: 27 Jun '17