Limits...
Golgi fragmentation in Alzheimer's disease.

Joshi G, Bekier ME, Wang Y - Front Neurosci (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular, Cellular and Developmental Biology, University of Michigan Ann Arbor, MI, USA.

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.

No MeSH data available.


Related in: MedlinePlus

Golgi Morphological and Functional Defects in AD. (A) Under normal conditions, the structure of the Golgi is maintained by active Golgi structural proteins such as GRASP65 (non-phosphorylated) and an intact microtubule (MT) network. Maintaining the Golgi structure is essential for proper trafficking and processing of APP and its processing enzymes. The majority of APP undergoes non-amyloidogenic processing, and cell-surface proteins, lipids, and polysaccharides, which are essential for neuronal function, are properly sorted and transported. Together, these factors maintain neuronal functionality and viability. (B) In AD, the Golgi is fragmented due to inactivation of Golgi structural proteins, such as degradation or phosphorylation of GRASP65 (pGRASP65), or tau hyper phosphorylation (pTau) and NFT formation that disrupt MT dynamics and protein trafficking. Golgi fragmentation impairs trafficking, processing, and sorting of APP and APP-processing enzymes, which stimulates amyloidogenic APP cleavage and further inactivates GRASP65. Additionally, Golgi fragmentation is predicted to alter trafficking, processing, and sorting of proteins, lipids, and polysaccharides that are essential for neuronal function; which could ultimately promote neuronal dysfunction and/or cell death.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4585163&req=5

Figure 1: Golgi Morphological and Functional Defects in AD. (A) Under normal conditions, the structure of the Golgi is maintained by active Golgi structural proteins such as GRASP65 (non-phosphorylated) and an intact microtubule (MT) network. Maintaining the Golgi structure is essential for proper trafficking and processing of APP and its processing enzymes. The majority of APP undergoes non-amyloidogenic processing, and cell-surface proteins, lipids, and polysaccharides, which are essential for neuronal function, are properly sorted and transported. Together, these factors maintain neuronal functionality and viability. (B) In AD, the Golgi is fragmented due to inactivation of Golgi structural proteins, such as degradation or phosphorylation of GRASP65 (pGRASP65), or tau hyper phosphorylation (pTau) and NFT formation that disrupt MT dynamics and protein trafficking. Golgi fragmentation impairs trafficking, processing, and sorting of APP and APP-processing enzymes, which stimulates amyloidogenic APP cleavage and further inactivates GRASP65. Additionally, Golgi fragmentation is predicted to alter trafficking, processing, and sorting of proteins, lipids, and polysaccharides that are essential for neuronal function; which could ultimately promote neuronal dysfunction and/or cell death.

Mentions: One neuropathological hallmark of AD is the formation of extracellular amyloid plaques by secreted amyloid beta (Aβ) peptides (Nelson et al., 2009), which is highly related to Golgi structure and function (Figure 1). Aβ is derived from the amyloid precursor protein (APP), a type I membrane protein that travels through the exocytic and endocytic pathways and undergoes sequential proteolysis by the action of β- and γ-secretases (Vassar et al., 1999). In neurons, APP is transported from the Golgi to many sub-cellular compartments (Haass et al., 1992), including the soma, dendrites and axons, through the exocytic and endocytic pathways. Despite the abundant literature demonstrating the critical role of endosomes in APP processing (for review see Suh and Checler, 2002; Small and Gandy, 2006), it has been indicated that the Golgi (in particular the trans-Golgi network) may be a site where Aβ is generated in the cell (Greenfield et al., 1999; Burgos et al., 2010; Choy et al., 2012). In addition, proper functioning of the Golgi is required for trafficking and maturation of both APP and its processing enzymes. For instance, the activity of the γ-secretase depends on the trafficking and maturation of nicastrin (Chung and Struhl, 2001) and other components of the γ-secretase complex through the Golgi (Herreman et al., 2003). Nicastrin is not catalytically active, but is important for the maturation and proper trafficking of the γ-secretase complex (Zhang et al., 2005). Nicastrin functions to stabilize presenilins (PSs), the catalytic subunit of the γ-secretase complex, and mediates PS trafficking to the cell surface by an unknown mechanism (Edbauer et al., 2002; Hu et al., 2002). Nicastrin also binds to the N-terminal domain of APP, and facilitates APP trafficking and cleavage (Yu et al., 2000; Kimberly et al., 2002). APP travels from the endoplasmic reticulum (ER) through the Golgi to the plasma membrane. The majority of APP localizes to the Golgi where it undergoes post-translational modifications and only a small fraction resides in the ER and the plasma membrane (Thinakaran and Koo, 2008). Finally, the α-secretatse ADAM10 is transported from dendritic Golgi outposts to synaptic membranes, a reaction modulated by the synapse-associated protein-97 (SAP97) (Saraceno et al., 2014). Thus, APP processing and Aβ production are intrinsically linked to the proper morphology and functionality of the Golgi.


Golgi fragmentation in Alzheimer's disease.

Joshi G, Bekier ME, Wang Y - Front Neurosci (2015)

Golgi Morphological and Functional Defects in AD. (A) Under normal conditions, the structure of the Golgi is maintained by active Golgi structural proteins such as GRASP65 (non-phosphorylated) and an intact microtubule (MT) network. Maintaining the Golgi structure is essential for proper trafficking and processing of APP and its processing enzymes. The majority of APP undergoes non-amyloidogenic processing, and cell-surface proteins, lipids, and polysaccharides, which are essential for neuronal function, are properly sorted and transported. Together, these factors maintain neuronal functionality and viability. (B) In AD, the Golgi is fragmented due to inactivation of Golgi structural proteins, such as degradation or phosphorylation of GRASP65 (pGRASP65), or tau hyper phosphorylation (pTau) and NFT formation that disrupt MT dynamics and protein trafficking. Golgi fragmentation impairs trafficking, processing, and sorting of APP and APP-processing enzymes, which stimulates amyloidogenic APP cleavage and further inactivates GRASP65. Additionally, Golgi fragmentation is predicted to alter trafficking, processing, and sorting of proteins, lipids, and polysaccharides that are essential for neuronal function; which could ultimately promote neuronal dysfunction and/or cell death.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4585163&req=5

Figure 1: Golgi Morphological and Functional Defects in AD. (A) Under normal conditions, the structure of the Golgi is maintained by active Golgi structural proteins such as GRASP65 (non-phosphorylated) and an intact microtubule (MT) network. Maintaining the Golgi structure is essential for proper trafficking and processing of APP and its processing enzymes. The majority of APP undergoes non-amyloidogenic processing, and cell-surface proteins, lipids, and polysaccharides, which are essential for neuronal function, are properly sorted and transported. Together, these factors maintain neuronal functionality and viability. (B) In AD, the Golgi is fragmented due to inactivation of Golgi structural proteins, such as degradation or phosphorylation of GRASP65 (pGRASP65), or tau hyper phosphorylation (pTau) and NFT formation that disrupt MT dynamics and protein trafficking. Golgi fragmentation impairs trafficking, processing, and sorting of APP and APP-processing enzymes, which stimulates amyloidogenic APP cleavage and further inactivates GRASP65. Additionally, Golgi fragmentation is predicted to alter trafficking, processing, and sorting of proteins, lipids, and polysaccharides that are essential for neuronal function; which could ultimately promote neuronal dysfunction and/or cell death.
Mentions: One neuropathological hallmark of AD is the formation of extracellular amyloid plaques by secreted amyloid beta (Aβ) peptides (Nelson et al., 2009), which is highly related to Golgi structure and function (Figure 1). Aβ is derived from the amyloid precursor protein (APP), a type I membrane protein that travels through the exocytic and endocytic pathways and undergoes sequential proteolysis by the action of β- and γ-secretases (Vassar et al., 1999). In neurons, APP is transported from the Golgi to many sub-cellular compartments (Haass et al., 1992), including the soma, dendrites and axons, through the exocytic and endocytic pathways. Despite the abundant literature demonstrating the critical role of endosomes in APP processing (for review see Suh and Checler, 2002; Small and Gandy, 2006), it has been indicated that the Golgi (in particular the trans-Golgi network) may be a site where Aβ is generated in the cell (Greenfield et al., 1999; Burgos et al., 2010; Choy et al., 2012). In addition, proper functioning of the Golgi is required for trafficking and maturation of both APP and its processing enzymes. For instance, the activity of the γ-secretase depends on the trafficking and maturation of nicastrin (Chung and Struhl, 2001) and other components of the γ-secretase complex through the Golgi (Herreman et al., 2003). Nicastrin is not catalytically active, but is important for the maturation and proper trafficking of the γ-secretase complex (Zhang et al., 2005). Nicastrin functions to stabilize presenilins (PSs), the catalytic subunit of the γ-secretase complex, and mediates PS trafficking to the cell surface by an unknown mechanism (Edbauer et al., 2002; Hu et al., 2002). Nicastrin also binds to the N-terminal domain of APP, and facilitates APP trafficking and cleavage (Yu et al., 2000; Kimberly et al., 2002). APP travels from the endoplasmic reticulum (ER) through the Golgi to the plasma membrane. The majority of APP localizes to the Golgi where it undergoes post-translational modifications and only a small fraction resides in the ER and the plasma membrane (Thinakaran and Koo, 2008). Finally, the α-secretatse ADAM10 is transported from dendritic Golgi outposts to synaptic membranes, a reaction modulated by the synapse-associated protein-97 (SAP97) (Saraceno et al., 2014). Thus, APP processing and Aβ production are intrinsically linked to the proper morphology and functionality of the Golgi.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular, Cellular and Developmental Biology, University of Michigan Ann Arbor, MI, USA.

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.

No MeSH data available.


Related in: MedlinePlus