ATL1 (atlastin GTPase 1) is a membrane-anchored GTPase that mediates GTP-dependent fusion of endoplasmic reticulum (ER) membranes, maintaining the continuous ER network architecture 1. ATL1 facilitates formation of three-way junctions where ER tubules intersect through a conserved molecular mechanism: two ATL1 molecules on neighboring ER tubules bind GTP and form homodimers via their G domains and 3HB regions 1. Upon GTP hydrolysis, the 3HB regions tighten, pulling membranes together to drive fusion; subsequent GDP release resets monomers for new fusion cycles 1. Beyond ER morphology, ATL1 regulates endosomal tubulation and lysosomal proteolysis in human neurons 2. ATL1 mutations represent a significant cause of hereditary spastic paraplegia (HSP-ATL1/SPG3A), with ATL1 mutations identified in >1% of HSP cases in large cohorts 3. De novo ATL1 variants cause early, complex symptoms extending beyond typical pure HSP, including neurodevelopmental abnormalities, upper limb spasticity, bulbar symptoms, and brain imaging abnormalities 4. ATL1 deficiency in human cortical neurons results in altered ER morphology with reduced three-way junctions, defective endosomal tubule dynamics, and impaired lysosomal function 2, linking ER morphology dysfunction to broader cellular proteolytic deficits in neurodegeneration.