A Golgi fragmentation pathway in neurodegeneration
Introduction
The Golgi apparatus is a cytoplasmic organelle involved in the transport, processing, and targeting of proteins synthesized in the rough endoplasmic reticulum and destined for the secretory pathway. In normal cells, the Golgi apparatus is composed of a series of flattened, parallel, interconnected cisternae organized around the microtubule-organizing center in the perinuclear region. The Golgi apparatus was originally thought to be a static organelle, but it is actually a highly dynamic structure. Examples of the Golgi’s dynamic behavior include its reversible disassembly during mitosis, when the Golgi apparatus fragments to produce clusters of vesicles that disperse throughout the cytoplasm (Robbins and Gonatas, 1964, Warren, 1993). These mitotic Golgi fragments are equally partitioned into the daughter cells. Upon exit from the mitotic program, the perinuclear Golgi apparatus is reconstituted simultaneously with the reformation of the nuclear envelope. Recent reports show that inhibition of Golgi fragmentation prevents entry into mitosis, suggesting that Golgi fragmentation is not merely a response to mitosis but a causal event in the process (Sutterlin et al., 2002).
It has also been reported that during apoptotic cell death of non-neuronal cells, Golgi stacks disperse and disassemble into tubulovesicular clusters, a process that bears some similarity to mitotic disassembly of the Golgi complex (Chiu et al., 2002, Lane et al., 2002, Machamer, 2003). Moreover, inhibiting caspase-mediated cleavage of the Golgi-associated protein Golgin-160 partially prevented cell death of these non-neuronal cells (Hicks and Machamer, 2005, Maag et al., 2005). Since the Golgi apparatus is involved in numerous important functions, such as the transport, processing, and targeting of proteins synthesized in the endoplasmic reticulum (ER), quality control of proteins in the Golgi apparatus and ER must be stringent to ensure appropriate cellular function. Thus, we reasoned that fragmentation of Golgi during cell death might have detrimental effects and lead to dysfunction of the cytoplasmic machinery in neurons as well as in non-neuronal cells. Along these lines, fragmentation of the Golgi apparatus has been reported in vivo in several human neurodegenerative diseases, including Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS) (Gonatas et al., 2006). Heretofore, however, it was not known if Golgi participate in a causal manner in the signaling cascade of cell death pathways. Here we present evidence that the Golgi apparatus is a sensor for controlling entry into apoptosis.
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Cell culture
Cerebrocortical neurons were isolated from embryonic day 15 or 16 rats and cultured as described (Budd et al., 2000). These cultures contain a mixture of cell types, including neurons, astrocytes, and microglia.
DNA constructs and transfection
DsRed2-mito expression constructs were purchased from Clontech. Mitofusin 1 (Mfn1) and Bax inhibitor-1 (BI-1) expression constructs were provided by M.T. Fuller (Stanford University) and John C. Reed (Burnham Institute for Medical Research), respectively. Grasp65 expression constructs
Fragmentation of the Golgi apparatus during neuronal injury
Given the potential importance of excitotoxins such as the neurotransmitter glutamate in contributing to neurodegenerative disorders (Lipton and Rosenberg, 1994), we initially tested the effects of this pathway on Golgi fragmentation. We found that excessive stimulation of NMDA-sensitive glutamate receptors resulted in neuronal injury preceded by Golgi fragmentation (Fig. 1). For these experiments, cerebrocortical neurons were transfected with a GFP vector fused with a mannosidase II
Discussion
Our findings suggest that the Golgi apparatus can sense and transduce death signals. Along these lines, Golgi fragmentation and dispersal, resulting from exposure to death signals, may be a harbinger for subsequent neuronal apoptosis. Similar to the ER and mitochondria, the Golgi complex may thus initiate stress signaling through its own unique molecular machinery. We found that several types of neuronal insult induce Golgi fragmentation, including excitotoxicity, reactive oxygen or nitrogen
Acknowledgments
This work was supported in part by NIH grants P01 HD29587, R01 EY05477, R01 EY09024, R01 NS043242, and R01 NS044326 (to S.A.L.), and R01 GM46224 and R01 GM56737 (to V.M.). S.A.L. was a Senior Scholar in Aging Research of the Ellison Medical Foundation. Additional support was provided by the NIH Blueprint Grant for La Jolla Interdisciplinary Neuroscience Center Cores P30 NS057096. We thank H. Fang for providing primary neuronal cultures, and T. Nakamura, J. Cui, G. Liot, H. Yuan. S. Graber, and
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