Article

A Golgi fragmentation pathway in neurodegeneration

Center for Neuroscience, Aging, and Stem Cell Research, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Neurobiology of Disease (Impact Factor: 5.2). 03/2008; 29(2):221-31. DOI: 10.1016/j.nbd.2007.08.015
Source: PubMed

ABSTRACT The Golgi apparatus processes intracellular proteins, but undergoes disassembly and fragmentation during apoptosis in several neurodegenerative disorders such as amyotrophic lateral sclerosis and Alzheimer's disease. It is well known that other cytoplasmic organelles play important roles in cell death pathways. Thus, we hypothesized that Golgi fragmentation might participate in transduction of cell death signals. Here, we found that Golgi fragmentation and dispersal precede neuronal cell death triggered by excitotoxins, oxidative/nitrosative insults, or ER stress. Pharmacological intervention or overexpression of the C-terminal fragment of Grasp65, a Golgi-associated protein, inhibits fragmentation and decreases or delays neuronal cell death. Inhibition of mitochondrial or ER cell death pathways also decreases Golgi fragmentation, indicating crosstalk between organelles and suggesting that the Golgi may be a common downstream-effector of cell death. Taken together, these findings implicate the Golgi as a sensor of stress signals in cell death pathways.

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    • "ER stress is a precursor of cell death in ALS (Atkin et al. 2006; Saxena et al. 2009) and can be caused by failure of ER-Golgi trafficking (Preston et al. 2009). The intact Golgi architecture is maintained by both anterograde (ER-Golgi) and retrograde (Golgi-ER) traffic and an imbalance in these processes leads to fragmentation of the Golgi (Nakagomi et al. 2008). Hence, impaired anterograde transport would also lead to fragmentation of the Golgi, and both ER stress and Golgi fragmentation occurred later than inhibition of VSVG-ts045 trafficking in the timecourse study. "
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    ABSTRACT: Cu/Zn-superoxide dismutase (SOD1) is misfolded in familial and sporadic Amyotrophic Lateral Sclerosis (ALS), but it is not clear how this triggers endoplasmic reticulum (ER) stress or other pathogenic processes. Here we demonstrate that mutant SOD1 (mSOD1) is predominantly found in the cytoplasm in neuronal cells. Furthermore, we show that mSOD1 inhibits secretory protein transport from the ER to Golgi apparatus. ER-Golgi transport is linked to ER stress, Golgi fragmentation and axonal transport and we also show that inhibition of ER-Golgi trafficking preceded ER stress, Golgi fragmentation, protein aggregation and apoptosis in cells expressing mSOD1. Restoration of ER-Golgi transport by over-expression of coatomer coat protein II (COPII) subunit Sar1 protected against inclusion formation and apoptosis, thus linking dysfunction in ER-Golgi transport to cellular pathology. These findings thus link several cellular events in ALS into a single mechanism occurring early in mSOD1 expressing cells. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 10/2013; 129(1). DOI:10.1111/jnc.12493 · 4.24 Impact Factor
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    • "Thus, either higher Salubrinal dose and/or longer follow-up may have revealed overt neuroprotection. In particular, Golgi fragmentation is an early precursor to cell death and neuronal health (Nakagomi et al., 2008). Thus, given that Salubrinal reduces Golgi fragmentation in αS expressing neurons, one may expect less ongoing neurodegeneration at later time points. "
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    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 03/2012; 32(10):3306-20. DOI:10.1523/JNEUROSCI.5367-11.2012 · 6.75 Impact Factor
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    • "Nakagomi et al. [21] have identified the fragmentation of the Golgi apparatus during apoptosis as a marker of some neurodegenerative diseases [21]. The results obtained have allowed us to demonstrate the onset of organelles alterations after cisPt treatment in B50 neuroblastoma rat cells. "
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    International Journal of Cell Biology 02/2012; 2012:424072. DOI:10.1155/2012/424072
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