Golgi disruption in neurodegenerative diseases
Golgi fragmentation has been observed for decades in neurons from patients and in animal models of neurodegenerative diseases, including amyotrophic lateral sclerosis, Alzheimer's disease, Creutzfeld-Jacob disease and spinocerebellar ataxia type 2 (Gonatas et al., 2006). But does the fragmentation induce neuron dysfunction or is it simply a downsteam effect? Most evidence suggests that Golgi disruption occurs prior to cell death or disease phenotypes. In cortical neurons undergoing excitotoxicity or oxidative or nitrosyl stress, Golgi fragmentation precedes cell death, and both fragmentation and death could be blocked when Golgi structure was rescued with expression of a C-terminal GRASP65 fragment (Nakagomi et al., 2008). The C-terminal GRASP65 fragment allows formation of GRASP oligomers but cannot be phosphorylated, which is required for disassembly. Golgi fragmentation usually results in decreased or blocked trafficking to the cell surface. This would be expected to impair cellular function and could contribute to apoptosis.
In cell and animal models of Alzheimer's disease, increased Aβ processing from the amyloid precursor protein (APP) leads to Golgi fragmentation before cell death (Gonatas et al., 2006). A recent study shows that phosphorylation of GRASP65 by Cdk5 activated by Aβ (possibly through calcium signaling) results in reversible disassembly of the Golgi complex (Joshi et al., 2014). By contrast to other situations where Golgi fragmentation results in decreased cargo trafficking, the Wang group has shown that Aβ-induced fragmentation actually increases cargo trafficking. This results either directly or indirectly in positive feedback, where production of Aβ is increased and thus increases Golgi fragmentation. However, increased Aβ processing may block further accumulation of Aβ. It was recently shown that the intracellular domain of APP (released after Aβ processing and translocated to the nucleus) leads to reduced levels of machinery required for APP trafficking out of the Golgi, and thus reduced production of Aβ (Ceglia et al., 2015). Clearly, there is still much to learn about the role of the Golgi complex in Alzheimer's disease.
ACBD3 (also known as GCP60) is upregulated in cell culture models expressing the huntingtin (Htt) protein with expanded polyglutamine repeats, as well as in the brains of mice that model Huntington disease and in the striatum of Huntington's patients (Sbodio et al., 2013). ACBD3 is a ubiquitous peripheral Golgi protein that interacts with golgins and may regulate trafficking of fragments of golgin-160 generated by caspase cleavage (Sbodio et al., 2006). Interestingly, as mentioned above, ACBD3 is one of the genes shown to be upregulated by Golgi stress induced by monensin (Oku et al., 2011), which requires TFE3 (Taniguchi et al., 2015). In striatal neurons, increased levels of ACBD3 may lead to increased neurotoxicity due to its interaction with both Rhes and Htt. Rhes is a small G protein that is associated with Htt pathogenicity. Rhes is specifically expressed in the striatum (unlike Htt, which is widely expressed) and is thus thought to limit the site of degeneration in Huntington's disease to this region of the brain. Caspase-2 cleavage of Htt has also been implicated in pathology (Hermel et al., 2004). It will be interesting to see if any other binding partners of ACBD3 and caspase-2 cleavage at the Golgi are involved in Huntington's pathology.