Faculty Collaboration Database

Diminished motor neuron activity driven by abnormal astrocytic EAAT1 glutamate transporter activity in spinal muscular atrophy is not fully restored after lentiviral SMN delivery. Glia 2023 May;71(5):1311-1332

Date

01/20/2023

Pubmed ID

36655314

DOI

10.1002/glia.24340

Scopus ID

2-s2.0-85146442117 (requires institutional sign-in at Scopus site)   3 Citations

Abstract

Spinal muscular atrophy (SMA) is characterized by the loss of the lower spinal motor neurons due to survival motor neuron (SMN) deficiency. The motor neuron cell autonomous and non-cell autonomous disease mechanisms driving early glutamatergic dysfunction, a therapeutically targetable phenotype prior to motor neuron cell loss, remain unclear. Using microelectrode array analysis, we demonstrate that the secretome and cell surface proteins needed for proper synaptic modulation are likely disrupted in human SMA astrocytes and lead to diminished motor neuron activity. While healthy astrocyte conditioned media did not improve SMA motor neuron activity, SMA motor neurons robustly responded to healthy astrocyte neuromodulation in direct contact cultures. This suggests an important role of astrocyte synaptic-associated plasma membrane proteins and contact-mediated cellular interactions for proper motor neuron function in SMA. Specifically, we identified a significant reduction of the glutamate Na⁺ dependent excitatory amino acid transporter EAAT1 within human SMA astrocytes and SMA lumbar spinal cord tissue. The selective inhibition of EAAT1 in healthy co-cultures phenocopied the diminished neural activity observed in SMA astrocyte co-cultures. Caveolin-1, an SMN-interacting protein previously associated with local translation at the plasma membrane, was abnormally elevated in human SMA astrocytes. Although lentiviral SMN delivery to SMA astrocytes partially rescued EAAT1 expression, limited activity of healthy motor neurons was still observed in SMN-transduced SMA astrocyte co-cultures. Together, these data highlight the detrimental impact of astrocyte-mediated disease mechanisms on motor neuron function in SMA and that SMN delivery may be insufficient to fully restore astrocyte function at the synapse.

Author List

Welby E, Ebert AD

Author

Allison D. Ebert 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
Glutamic Acid
Humans
Motor Neurons
Muscular Atrophy, Spinal
Survival of Motor Neuron 1 Protein
Transcription Factors