ER-shaping proteins are required for ER and mitochondrial network organization in motor neurons

Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative disorders characterized by degeneration of the longest motor neurons in the corticospinal tract, leading to muscle weakness and spasticity of the lower limbs. Pathogenic variants in genes encoding proteins that shape the endoplasmic-reticulum (ER) network are a leading cause of HSP, however, the mechanisms by which loss of ER-shaping proteins underpin degeneration of selective neurons in HSP remain poorly understood. To begin to address this, we have generated a novel in vivo model of HSP in Drosophila melanogaster by targeted knockdown of the ER-shaping protein Arl6IP1 Variants in the human homolog of this gene have recently been linked to HSP subtype SPG61. Arl6IP1 RNAi flies display progressive locomotor deficits without a marked reduction in lifespan, recapitulating key features of HSP in human patients. Loss of Arl6IP1 leads to fragmentation of the smooth ER and disrupted mitochondrial network organization within the distal ends of long motor neurons. Furthermore, genetically increasing mitochondrial fission, by overexpression of dynamin-related protein 1 (Drp1), restores mitochondrial network organization and rescues locomotor deficits in two independent Drosophila models of HSP. Taken together, these results propose a role for ER-shaping proteins in mitochondrial network organization in vivo and suggest that impaired mitochondrial organization may be a common mechanism underpinning some forms of HSP.