Diminished motor neuron activity driven by abnormal astrocytic GLAST glutamate transporter activity in spinal muscular atrophy is not fully restored after lentiviral SMN delivery

Author:

Welby Emily,Ebert Allison D.

Abstract

AbstractSpinal muscular atrophy (SMA) is a pediatric neuromuscular disease characterized by the loss of the lower spinal motor neurons due to survival motor neuron (SMN) deficiency. Motor neuron dysfunction at the glutamatergic afferent synapse is observed during early stages of SMA disease progression, which could be targeted therapeutically prior to cell death. However, the motor neuron cell autonomous and non-cell autonomous disease mechanisms driving this phenotype remain unclear. Our study reveals a non-cell autonomous SMN-associated disease mechanism affecting glutamate transporter (GLAST) activity in astrocytes that contributes to human motor neuron dysfunction in SMA. Transcriptomic analysis of SMA patient human induced pluripotent stem cell (iPSC)-derived astrocytes identified a significant downregulation of genes associated with astrocytic regulation of the synapse, including glutamate neurotransmission. This finding was substantiated by our microelectrode array analysis of motor neuron activity, which was severely diminished specifically in the presence of patient-derived astrocytes. Co-culturing patient-derived motor neurons with healthy-derived astrocytes showed comparable firing rates and bursting activity to healthy-derived motor neurons, suggesting diminished neural activity is an astrocyte-mediated phenotype in this system. Towards defining astrocyte-intrinsic defects that could induce motor neuron dysfunction, we identified abnormally low levels of excitatory amino acid transporter (EAAT1/GLAST) in patient-derived astrocytes, which when selectively inhibited in healthy co-cultures could phenocopy the diminished neural activity previously observed in patient-derived co-cultures. Caveolin-1, an SMN-interacting lipid raft protein associated with glutamate transporter regulation, showed increased protein levels and accumulation in patient astrocytes. Both GLAST and caveolin-1 phenotypes could be partially rescued via lentiviral-mediated SMN re-expression in patient astrocytes. Together, our work defines a novel SMN-associated disease mechanism involving abnormal glutamate transporter activity and regulation in astrocytes that can directly diminish motor neuron function in SMA.

Publisher

Cold Spring Harbor Laboratory

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3