Wednesday, July 6, 2022
Mitochondrial Health

Astrocyte mitochondria support motor circuit function in a Drosophila model of ALS

Sonja Zolnoski – “Astrocyte mitochondria support motor circuit function in a Drosophila model of ALS”
ALS is a disease where selective degeneration of motor neurons (MNs) causes death. Although ALS is considered a MN disease, dysregulation of neighboring glial cells contributes to ALS in animal models. Astrocytes are a predominant glial cell type that send fine projections to neuronal synapses and metabolically support neurons. Indeed, electron microscopy has identified mitochondria in astrocytic processes. We hypothesize that failure of astrocyte mitochondrial trafficking to synapses contributes to MN loss in ALS. We used in vivo imaging to assay MN activity following astrocyte-specific knockdown (KD) of the ALS-causing gene tbph and observed ectopic MN signaling and increases in MN synapses at the neuromuscular junction (NMJ), resulting in altered locomotor behavior in a Drosophila model of ALS. Accordingly, we saw an increased prevalence of astrocyte mitochondria co-localized with synapses on MN dendrites, which could be further increased by optogenetic activation of MNs. Through genetic screening, we identified the mitochondrial adaptor protein, Milton, as essential for astrocyte mitochondrial trafficking. Astrocyte KD of Milton using RNAi caused failure of mitochondria to traffic to MN synapses, as well as similar changes to NMJ ultrastructure and locomotor function as seen following tbph KD. Through further study, we hope to inform our understanding of the etiology of ALS and move towards successful therapeutic strategies.


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