ER fusogens maintain membrane reservoir to ensure brain function

Abstract

How the morphological dynamics of the endoplasmic reticulum (ER) are linked to its functions is unclear. Atlastins (ATLs), a class of GTPases, mediate ER fusion, and human mutations in ATL1 cause hereditary spastic paraplegia (HSP). Here, we show that ATL2-knockout mice are embryonic lethal with compromised development, particularly of the cerebellum. ATL2 is highly expressed in neuroglia, though ATL1 is dominant in the brain. Lack of ATL2 disorganizes the positioning of Bergmann glia, which in turn interferes with granule cell migration. These cells have significant shrinkage in the intracellular membrane area, which is associated with decreased phosphatidylcholine and cholesterol synthesis. When tested in calyx-type synapses in ATL-deleted mice, a reduced membrane reservoir, represented by fewer presynaptic vesicles, leads to defective synaptic function and deafness. Collectively, these findings suggest that ER-shaping activity by ATL is essential for sustained lipid synthesis, and boosted lipid uptake is potentially beneficial for HSP patients.