# ER Morphology in the Pathogenesis of Hereditary
## 3 ER Shaping Proteins
### Atlastin-1 (SPG3a)
No other activities have been associated with this protein. Consequently, it can be assumed that pathological mutation of ATL1 would interfere with the establishment and/or maintenance of proper ER morphology through perturbation of membrane fusion. Nevertheless, the available data have only provided circumstantial experimental support in favor of this hypothesis. Although this may be due in part to the lack of suitable animal models, the main reason may be more related to the challenges associated with imaging the complex structure of the neuronal ER in vivo to determine morphological differences between wild-type and mutant ER, which are still insurmountable. The uncertainty regarding the consequences induced by ATL1 mutation in the neuronal ER, has led to questioning the idea that SPG3A mutations cause HSP exclusively by disrupting membrane fusion and ER morphogenesis [50]. An alternative possibility is that atlastins are indeed directly involved only in membrane fusion but indirectly implicated in other ER-related cellular processes whose disruption eventually leads to disease even when ER shape is not visibly affected. The ER is responsible for protein synthesis, modification and quality control, and plays crucial roles in carbohydrate metabolism, control of lipid synthesis and delivery, formation of other membrane-bound organelles, and lipid droplets as well as Ca\({}^{2+}\) homeostasis [55; 56]. Fusion impairment below the current threshold of detection, such as that probably caused by dominant mutation of ATL1, could then affect, in ways that we still do not understand, one or several ER functions. ATL2 GTPase activity has been reported to contribute to IP3-induced dendritic Ca\({}^{2+}\) signals in primary hippocampal neurons [57] and depletion of ATLs affects store-operated Ca\({}^{2+}\) entry in PC-12 cells [58], hinting that atlastins may influence Ca\({}^{2+}\) homeostasis. This notion may be supported by a report that Atlastin-1 modulates seizure activity and neuronal excitability [59] and the observation that _Drosophila_ atlastin decreases evoked transmitter release at the neuromuscular junction and causes age-dependent decline in adult locomotion [57; 60], even though both works surmise that interference with BMP trafficking could also be a potential source of these phenotypes, conceivably suggesting that perturbation of trafficking could underlie HSP-disease. Indeed,HSP-causing mutations were shown to disrupt BMP receptors II trafficking to the cell surface in HEK239-T cells [61] and knockdown of zebrafish atl1 decreases larval mobility, perturbs the architecture of spinal motor axons and is associated with a substantial upregulation of the BMP signaling pathway, again implying that atlastins may regulate BMP receptor trafficking [62]. Another possible mechanism of SPG3A disease, linked but secondary to membrane fusion, is the regulation of lipid droplet size. In fact, gain- and loss-of-function studies in _C. elegans_, _Drosophila_, and mammalian cells have suggested that the atlastins affect LD size, most likely in an indirect manner, through their ER membrane fusion activity [63]. Additionally, all atlastins have been implicated in ER-phag where their role requires a functional GTPase domain and proper ER localization [64] and ATL3 functions specifically as a receptor for GABARP during ER-phag, with HSAN-associated ATL3 mutations disrupting association with GABARP and impairing ATL3 function in ER-phag [65]. In conclusion, while several different pathways could lead secondarily to atlastins-associated disease, the ability to catalyze membrane fusion is the only function demonstrated for atlastin(s) to date and evidence-based mechanistic links between fusion and other proposed disease pathways leading to HSP have not been corroborated making defects in membrane fusion the most likely route to SPG3A disease.