Faculty Collaboration Database

Astrocyte-produced miR-146a as a mediator of motor neuron loss in spinal muscular atrophy. Hum Mol Genet 2017 Sep 01;26(17):3409-3420

Date

06/24/2017

Pubmed ID

28637335

DOI

10.1093/hmg/ddx230

Scopus ID

2-s2.0-85040601550 (requires institutional sign-in at Scopus site)   55 Citations

Abstract

Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, is caused by the loss of the survival motor neuron-1 (SMN1) gene, which leads to motor neuron loss, muscle atrophy, respiratory distress, and death. Motor neurons exhibit the most profound loss, but the mechanisms underlying disease pathogenesis are not fully understood. Recent evidence suggests that motor neuron extrinsic influences, such as those arising from astrocytes, contribute to motor neuron malfunction and loss. Here we investigated both loss-of-function and toxic gain-of-function astrocyte mechanisms that could play a role in SMA pathology. We had previously found that glial derived neurotrophic factor (GDNF) is reduced in SMA astrocytes. However, reduced GDNF expression does not play a major role in SMA pathology as viral-mediated GDNF re-expression did not improve astrocyte function or motor neuron loss. In contrast, we found that SMA astrocytes increased microRNA (miR) production and secretion compared to control astrocytes, suggesting potential toxic gain-of-function properties. Specifically, we found that miR-146a was significantly upregulated in SMA induced pluripotent stem cell (iPSC)-derived astrocytes and SMNΔ7 mouse spinal cord. Moreover, increased miR-146a was sufficient to induce motor neuron loss in vitro, whereas miR-146a inhibition prevented SMA astrocyte-induced motor neuron loss. Together, these data indicate that altered astrocyte production of miR-146a may be a contributing factor in astrocyte-mediated SMA pathology.

Author List

Sison SL, Patitucci TN, Seminary ER, Villalon E, Lorson CL, Ebert AD

Authors

Allison D. Ebert PhD Associate Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
Teresa Patitucci PhD Associate Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Astrocytes
Disease Models, Animal
Humans
Induced Pluripotent Stem Cells
Mice
MicroRNAs
Motor Neurons
Muscular Atrophy, Spinal
Nerve Degeneration
Spinal Cord
Survival of Motor Neuron 1 Protein
Survival of Motor Neuron 2 Protein
Up-Regulation