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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

Mechanism of Golgi defects in AD. Increased BACE1 activity and/or decreased Aβ clearance from the extracellular space leads to the accumulation of Aβ. In turn, Aβ induces Ca2+ influx, which activates Calpain and induces cleavage of p35 to p25. Consequently, p25 activates CDK5, which in turn phosphorylates and inactivates the Golgi structural protein GRASP65 (i.e., pGRASP65). Inactivation of GRASP65 causes Golgi fragmentation, which alters trafficking of APP, and potentially the secretases, leading to increased Aβ production. This deleterious feedback loop (indicated by black arrows) would impair the integrity of the secretory pathway for sorting, trafficking and modifications of many essential proteins, which may compromise neuronal function, activate inflammatory responses, or cause neuronal cell death. Inhibition of CDK5 or expression of non-phosphorylatable GRASP65 mutants restores the normal Golgi morphology and reduces APP trafficking and Aβ production (indicated by green arrows). Therefore, rescue of the defective Golgi may delay AD development.
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Figure 2: Mechanism of Golgi defects in AD. Increased BACE1 activity and/or decreased Aβ clearance from the extracellular space leads to the accumulation of Aβ. In turn, Aβ induces Ca2+ influx, which activates Calpain and induces cleavage of p35 to p25. Consequently, p25 activates CDK5, which in turn phosphorylates and inactivates the Golgi structural protein GRASP65 (i.e., pGRASP65). Inactivation of GRASP65 causes Golgi fragmentation, which alters trafficking of APP, and potentially the secretases, leading to increased Aβ production. This deleterious feedback loop (indicated by black arrows) would impair the integrity of the secretory pathway for sorting, trafficking and modifications of many essential proteins, which may compromise neuronal function, activate inflammatory responses, or cause neuronal cell death. Inhibition of CDK5 or expression of non-phosphorylatable GRASP65 mutants restores the normal Golgi morphology and reduces APP trafficking and Aβ production (indicated by green arrows). Therefore, rescue of the defective Golgi may delay AD development.

Mentions: The mechanism of Golgi fragmentation in AD has not been well studied, but likely involves multiple mechanisms (Figure 1). One possibility is through the disruption of the microtubule network by tau precipitation and NFT formation (Liazoghli et al., 2005). Microtubule defects may affect both the central localization of the Golgi in the cell and ER-Golgi-plasma membrane trafficking that indirectly impacts the size and morphology of the Golgi (Fokin et al., 2014). Tau could also affect vesicle trafficking by inhibiting the binding of motor proteins such as kinesins to microtubules (Seitz et al., 2002). Another possibility is through modulation of Golgi structural proteins (Figure 2). Both mitotic phosphorylation and apoptotic cleavage of Golgi proteins results in Golgi fragmentation (Wang and Seemann, 2011). For instance, GRASP65 is phosphorylated by mitotic kinases Cdk1 and Polo-like kinase (Plk1) during mitosis (Wang et al., 2003) and cleaved by caspase-3 in apoptosis (Lane et al., 2002), both of which cause Golgi fragmentation (Tang et al., 2008; Wang and Seemann, 2011). In tissue culture and mouse models of AD, GRASP65 phosphorylation was implicated as a major cause of Golgi fragmentation (Joshi et al., 2014; Joshi and Wang, 2015). At the molecular level, Aβ accumulation triggers Ca2+ influx (Zempel et al., 2010), which activates Calpain, a protease known to increase the cleavage of p35 to p25 (Lee et al., 2000), p25 then activates Cdk5. It has been previously reported that p35 and Cdk5 are associated with Golgi membranes and regulate membrane traffic (Paglini et al., 2001). Subsequently, Cdk5 (also known to phosphorylate tau in AD) phosphorylates GRASP65, which negatively regulates GRASP65, leading to Golgi fragmentation. Consequently, Golgi fragmentation enhances APP trafficking and increases Aβ production (Joshi et al., 2014). Fragmentation of the Golgi was rapidly reversible by the use of Cdk5-specific inhibitors, or by expression of non-phosphorylatable GRASP proteins, both of which significantly reduced APP trafficking and Aβ production (Figure 2). In the same study, degradation of Golgi structural proteins was not detected (Joshi et al., 2014). These results suggest that Golgi fragmentation in AD, at least in the early stage, is caused by phosphorylation of Golgi structural proteins, an event that occurs in parallel with tau hyper-phosphorylation during the development of the disease. Overall, the causes of Golgi structural defects in AD are expected to be manifold and require further investigation to determine the precise mechanisms.


Golgi fragmentation in Alzheimer's disease.

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

Mechanism of Golgi defects in AD. Increased BACE1 activity and/or decreased Aβ clearance from the extracellular space leads to the accumulation of Aβ. In turn, Aβ induces Ca2+ influx, which activates Calpain and induces cleavage of p35 to p25. Consequently, p25 activates CDK5, which in turn phosphorylates and inactivates the Golgi structural protein GRASP65 (i.e., pGRASP65). Inactivation of GRASP65 causes Golgi fragmentation, which alters trafficking of APP, and potentially the secretases, leading to increased Aβ production. This deleterious feedback loop (indicated by black arrows) would impair the integrity of the secretory pathway for sorting, trafficking and modifications of many essential proteins, which may compromise neuronal function, activate inflammatory responses, or cause neuronal cell death. Inhibition of CDK5 or expression of non-phosphorylatable GRASP65 mutants restores the normal Golgi morphology and reduces APP trafficking and Aβ production (indicated by green arrows). Therefore, rescue of the defective Golgi may delay AD development.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 2: Mechanism of Golgi defects in AD. Increased BACE1 activity and/or decreased Aβ clearance from the extracellular space leads to the accumulation of Aβ. In turn, Aβ induces Ca2+ influx, which activates Calpain and induces cleavage of p35 to p25. Consequently, p25 activates CDK5, which in turn phosphorylates and inactivates the Golgi structural protein GRASP65 (i.e., pGRASP65). Inactivation of GRASP65 causes Golgi fragmentation, which alters trafficking of APP, and potentially the secretases, leading to increased Aβ production. This deleterious feedback loop (indicated by black arrows) would impair the integrity of the secretory pathway for sorting, trafficking and modifications of many essential proteins, which may compromise neuronal function, activate inflammatory responses, or cause neuronal cell death. Inhibition of CDK5 or expression of non-phosphorylatable GRASP65 mutants restores the normal Golgi morphology and reduces APP trafficking and Aβ production (indicated by green arrows). Therefore, rescue of the defective Golgi may delay AD development.
Mentions: The mechanism of Golgi fragmentation in AD has not been well studied, but likely involves multiple mechanisms (Figure 1). One possibility is through the disruption of the microtubule network by tau precipitation and NFT formation (Liazoghli et al., 2005). Microtubule defects may affect both the central localization of the Golgi in the cell and ER-Golgi-plasma membrane trafficking that indirectly impacts the size and morphology of the Golgi (Fokin et al., 2014). Tau could also affect vesicle trafficking by inhibiting the binding of motor proteins such as kinesins to microtubules (Seitz et al., 2002). Another possibility is through modulation of Golgi structural proteins (Figure 2). Both mitotic phosphorylation and apoptotic cleavage of Golgi proteins results in Golgi fragmentation (Wang and Seemann, 2011). For instance, GRASP65 is phosphorylated by mitotic kinases Cdk1 and Polo-like kinase (Plk1) during mitosis (Wang et al., 2003) and cleaved by caspase-3 in apoptosis (Lane et al., 2002), both of which cause Golgi fragmentation (Tang et al., 2008; Wang and Seemann, 2011). In tissue culture and mouse models of AD, GRASP65 phosphorylation was implicated as a major cause of Golgi fragmentation (Joshi et al., 2014; Joshi and Wang, 2015). At the molecular level, Aβ accumulation triggers Ca2+ influx (Zempel et al., 2010), which activates Calpain, a protease known to increase the cleavage of p35 to p25 (Lee et al., 2000), p25 then activates Cdk5. It has been previously reported that p35 and Cdk5 are associated with Golgi membranes and regulate membrane traffic (Paglini et al., 2001). Subsequently, Cdk5 (also known to phosphorylate tau in AD) phosphorylates GRASP65, which negatively regulates GRASP65, leading to Golgi fragmentation. Consequently, Golgi fragmentation enhances APP trafficking and increases Aβ production (Joshi et al., 2014). Fragmentation of the Golgi was rapidly reversible by the use of Cdk5-specific inhibitors, or by expression of non-phosphorylatable GRASP proteins, both of which significantly reduced APP trafficking and Aβ production (Figure 2). In the same study, degradation of Golgi structural proteins was not detected (Joshi et al., 2014). These results suggest that Golgi fragmentation in AD, at least in the early stage, is caused by phosphorylation of Golgi structural proteins, an event that occurs in parallel with tau hyper-phosphorylation during the development of the disease. Overall, the causes of Golgi structural defects in AD are expected to be manifold and require further investigation to determine the precise mechanisms.

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