Golgi fragmentation in Alzheimer's disease

Abstract

The Golgi apparatus is an essential cellular organelle for post-translational modifications, sorting, and trafficking of membrane and secretory proteins. Proper functionality of the Golgi requires the formation of its unique cisternal-stacking morphology. The Golgi structure is disrupted in a variety of neurodegenerative diseases, suggesting a common mechanism and contribution of Golgi defects in neurodegenerative disorders. A recent study on Alzheimer's disease (AD) revealed that phosphorylation of the Golgi stacking protein GRASP65 disrupts its function in Golgi structure formation, resulting in Golgi fragmentation. Inhibiting GRASP65 phosphorylation restores the Golgi morphology from Aβ-induced fragmentation and reduces Aβ production. Perturbing Golgi structure and function in neurons may directly impact trafficking, processing, and sorting of a variety of proteins essential for synaptic and dendritic integrity. Therefore, Golgi defects may ultimately promote the development of AD. In the current review, we focus on the cellular impact of impaired Golgi morphology and its potential relationship to AD disease development.

Morphometric alterations of Golgi apparatus in Alzheimer's disease are related to tau hyperphosphorylation

“…Indeed, trafficking and maturation of APP, its processing enzymes and Aβ production have been shown to be dependent on the integrity of the GA (Burgos et al, 2010, Choy et al, 2012, Greenfield et al, 1999, Huse et al, 2002, Joshi et al, 2015, Joshi and Wang, 2015). In addition, in the APPswe/PS1ΔE9 animal model of AD, it has been reported that the accumulation Aβ peptide in neurons might induce GA fragmentation, thereby accelerating the traffic of APP and the production of Aβ (Joshi et al, 2015, Joshi and Wang, 2015). …”

“…Proper functioning of the GA is necessary for Aβ production and for trafficking and maturation of amyloid precursor protein APP and its processing enzymes (Burgos et al, 2010, Choy et al, 2012, Greenfield et al, 1999, Huse et al, 2002, Joshi et al, 2015). In addition, studies using the APPswe/PS1ΔE9 animal model of the disease have reported that the accumulation of Aβ peptides leads to Golgi fragmentation, mediated by cdk5-dependent phosphorylation of Grasp 65, which in turn accelerates APP trafficking and Aβ production (Joshi et al, 2015, Joshi and Wang, 2015).…”

“…In addition, studies using the APPswe/PS1ΔE9 animal model of the disease have reported that the accumulation of Aβ peptides leads to Golgi fragmentation, mediated by cdk5-dependent phosphorylation of Grasp 65, which in turn accelerates APP trafficking and Aβ production (Joshi et al, 2015, Joshi and Wang, 2015). Furthermore, the integrity of the microtubule (Burkhardt, 1998, Cole et al, 1996) and actin (Egea et al, 2006) cytoskeleton is necessary for the maintenance of the structural characteristics and the positioning of the GA.…”

Glycosylation Quality Control by the Golgi Structure

“…This finding is relevant to human disorders where the Golgi structure is fragmented. In Alzheimer’s disease, Golgi fragmentation resulted from GRASP65 phosphorylation by activated Cdk5 accelerated the trafficking of the amyloid precursor protein (APP) and thus increases amyloid beta (Aβ) production, which could be reversed by expressing non-phosphorylatable GRASP proteins [78–80]. …”

Golgi apparatus self-organizes into the characteristic shape via postmitotic reassembly dynamics

“…A typical morphological anomaly of the Golgi apparatus is fragmentation, which is observed in Golgi-associated protein deletion mutants, stress-exposed cells, and diseases (5)(6)(7)(8)(9)(10). Via the fragmentation, Golgi components completely decompose and lose their morphological characteristics such as the structural anisotropy and long-range coherence.…”