# ER Morphology in the Pathogenesis of Hereditary
## 5 ER-Golgi Trafficking  
Proper intracellular trafficking is essential for neuronal development and function [139] and neurons appear particularly sensitive to defects in trafficking [140]. Indeed, early secretory compartments ER, ER-exit sites (ERES) and ER-Golgi intermediate compartment (ERGIC) are distributed throughout the soma, dendrites and axon, while the Golgi apparatus and Golgi outposts are found only in the somatodendritic compartment and are excluded from axons [141]. Thus the trafficking to specific neuronal domains must be finely regulated for proper neuronal function and dysregulation of this process may contribute to neurological disease pathogenesis. Mutations in genes involved in ER-Golgi trafficking have also been associated with HSP [139; 140; 142].  
Anteorgrade ER-to-Golgi transport requires COPII-coated vesicles that form at ERES [143]. ERES-generated COPII vesicles are directed towards ERGIC, from where cargo proteins can be sorted to the Golgi apparatus, retained in the ERGIC or sent back to the ER [144].  
In addition to ERES, COPII vesicles can bud from ER-phag sites (ERPHS) and then be sorted to autophagosomes [145].  
Several ERES constituents act as regulators for subunit recruitment and complex stabilization [144]. Among these interactors, the TRK-fused gene (TFG, _SPG57_) protein [146; 19] and the Tectonin Beta-Propeller Repeat Containing 2 (TECPR2, OMIM _SPG49_) protein [18] have been associated with complicated forms of HSP when mutated. TFG interacts directly with the scaffolding protein Sec16 [147] and ER morphology and distribution were found altered in TFG-depleted COS-7 cells [19]. TECCPR2 is a Atg8-binding partner for autophagy [18; 148] thought to be required for COPII-dependent cargo export from ER to Golgi [140; 149]. HSP patient fibroblasts carrying mutant TECCPR2 showed delayed ER export [149]. Consistently, TECPR2 depletion in mammalian cells reduced ERES number [149] and led to the expansion of ER sheets, suggesting a link between ER-Golgi transport and maintenance of ER morphology [149]. TECPR2 depletion has been shown to block the delivery to the Golgi apparatus of glycosylphosphatidyldilinositol (GPI)-anchored proteins (GPI-APs) [149; 150]. GPI deacylation is crucial for efficient transport of GPI-APs from the ER to the Golgi [151]. Intriguingly, SPG67 is caused by an autosomal recessive mutation in the gene coding for the post-GPI attachment to proteins inositol Deacylase 1 (PGAP1) [13], an ER membrane protein required for GPI-APs deacylation.  
Pathological mutations engineered in the endogenous _Drosophila_ altasthin gene impacted Golgi structure in neurons [52], and transfection of mutant ATL1 in HEK293 cells prevented Golgi maturation [152]. A reduction in the efficiency of cargo packaging into COPII vesicles and delayed cargo delivery to Golgi has been observed upon ATLs depletion/mutation both in mammalian [153; 154] and plant cells [155], potentially underscoring the importance of the connection between ER shape and function.  
In addition to the classical COPI-coated vesicle-dependent retrograde Golgi to ER transport [154], a COPI-independent pathway has been described [154; 156; 157]. In particular, cytoskeleton-based mechanisms are suggested to participate in this process through the repositioning of Golgi membranes [158]. KIF1C (_SPG58_) is a MT-binding protein belonging to kinesin superfamily that has been found mutated in HSP [159]. KIF1C participates in Golgi-to-ER trafficking [160] and appears to function in the maintenance of Golgi structure, since its depletion has been reported to cause Golgi fragmentation in HeLa cells [159; 161]. Two other kinesins have been found mutated in HSP, KIFSA (_SPG10_) [162; 163] and KIF1A (_SPG30_) [17; 164], but they are involved in axonal organelle transport [165; 166], possibly affecting ER positioning rather than ER-to-Golgi transport.