The delivery of survival motor neuron (SMN) protein to spinal muscular atrophy (SMA) astrocytes partially rescues the expression of EAAT1, a glutamate Na+ dependent excitatory amino acid transporter, found a new study by American researchers. However, this only led to limited healthy motor neuron activity, suggesting a novel disease mechanism associated with SMN that involves abnormal astrocyte glutamate transporter activity.
“As novel therapies for SMA progress and long-term effects of FDA-approved treatments are assessed in patients, our work highlights the importance of early therapeutic intervention to promote glial cell health and tracking improvements in glial-mediated neuromodulation,” the study authors wrote.
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The study is published in the journal Glia.
Their work demonstrated that the proteins found on the cell surface, which are necessary for proper synaptic function are likely disrupted in SMA astrocytes, resulting in reduced motor neuron activity.
The team from the Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin in Milwaukee found that when they used media conditioned with healthy astrocytes, the activity of SMA motor neurons did not improve. However, when they used direct contact cultures for astrocyte neuromodulation, SMA motor neurons responded robustly.
“This suggests an important role of astrocyte synaptic-associated plasma membrane proteins and contact-mediated cellular interactions for proper motor neuron function in SMA,” the researchers concluded.
They found that EAAT1 was significantly reduced in human SMA astrocytes and SMA lumbar spinal cord tissue while caveolin-1 was abnormally elevated. (Caveolin-1 is a protein that interacts with SMN that was previously thought to be associated with local translation at the plasma membrane). When they selectively inhibited EAAT1 in healthy cocultures, the researchers found that neural activity was reduced similar to what is observed in SMA astrocyte cocultures.
“Together, these data highlight the detrimental impact of astrocyte-mediated disease mechanisms on motor neuron function in SMA,” the researchers concluded.
Welby E, Ebert AD. 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. Published online January 18, 2023. doi:10.1002/glia.24340