Abstract
Amyotrophic Lateral Sclerosis (ALS) is an invariably fatal neurodegenerative disorder, which specifically targets motor neurons in the brain, brain stem and spinal cord. Whilst the etiology of ALS remains unknown, fragmentation of the Golgi apparatus is detected in ALS patient motor neurons and in animal/cellular disease models. The Golgi is a highly dynamic organelle that acts as a dispatching station for the vesicular transport of secretory/transmembrane proteins. It also mediates autophagy and maintains endoplasmic reticulum (ER) and axonal homeostasis. Both the trigger for Golgi fragmentation and the functional consequences of a fragmented Golgi apparatus in ALS remain unclear. However, recent evidence has highlighted defects in vesicular trafficking as a pathogenic mechanism in ALS. This review summarizes the evidence describing Golgi fragmentation in ALS, with possible links to other disease processes including cellular trafficking, ER stress, defective autophagy, and axonal degeneration.
Highlights
The Golgi apparatus acts as a dispatching station whereby proteins and lipids newly synthesized in the endoplasmic reticulum (ER) are transported to the endosomal system, secretory granules, or plasma membrane
Secretory protein cargo buds from the ER via coat protein complex II (COPII) coated vesicles, to form tubulovesicular structures known as the ER-Golgi intermediate compartment (ERGIC), which eventually fuse with the cis-Golgi (Appenzeller-Herzog and Hauri, 2006)
More recently we demonstrated that mutant forms of both fused in sarcoma (FUS) and TDP-43 impair the incorporation of secretory cargo into COPII vesicles budding off from the ER, impeding protein export from the ER, while mutant superoxide dismutase 1 (SOD1) was shown to inhibit ERGIC-Golgi trafficking by destabilizing microtubules (Soo et al, 2015a)
Summary
The Golgi apparatus (referred to as “Golgi” hereafter) acts as a dispatching station whereby proteins and lipids newly synthesized in the ER are transported to the endosomal system, secretory granules, or plasma membrane. Dysfunction to proteostasis includes protein misfolding and aggregation, ER stress, Golgi fragmentation, autophagy dysfunction, inhibition of cellular trafficking, and axonal degeneration. Mutations in proteins involved in endosomal sorting and trafficking which are required for the formation of autophagosomes (VCP, p62, dynactin, and RAB7) are associated with ALS (Otomo et al, 2012).
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