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: 5.08). 03/2008; 29(2):221-31. DOI: 10.1016/j.nbd.2007.08.015
Source: PubMed


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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    • "Its morphology depends on a large variety of protein components and cellular processes [9-13]. Accordingly, Golgi morphology can alter under a variety of physiological conditions such as cell division, growth, and altered metabolic demands [9], as well as pathological conditions, including impaired ER function, disruption of intracellular transport, altered lipid metabolism, excessive excitation, DNA damage, and activation of cell death pathways [6,14-19]. "
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    ABSTRACT: Fragmentation of stacked cisterns of the Golgi apparatus into dispersed smaller elements is a feature associated with degeneration of neurons in amyotrophic lateral sclerosis (ALS) and some other neurodegenerative disorders. However, the role of Golgi fragmentation in motor neuron degeneration is not well understood. Here we use a SOD1-ALS mouse model (low-copy Gurney G93A-SOD1 mouse) to show that motor neurons with Golgi fragmentation are retrogradely labeled by intramuscularly injected CTB (beta subunit of cholera toxin), indicating that Golgi fragmentation precedes neuromuscular denervation and axon retraction. We further show that Golgi fragmentation may occur in the absence of and precede two other pathological markers, i.e. somatodendritic SOD1 inclusions, and the induction of ATF3 expression. In addition, we show that Golgi fragmentation is associated with an altered dendritic organization of the Golgi apparatus, does not depend on intact apoptotic machinery, and is facilitated in transgenic mice with impaired retrograde dynein-dependent transport (BICD2-N mice). A connection to altered dynein-dependent transport also is suggested by reduced expression of endosomal markers in neurons with Golgi fragmentation, which also occurs in neurons with impaired dynein function. Together the data indicate that Golgi fragmentation is a very early event in the pathological cascade in ALS that is associated with altered organization of intracellular trafficking.
    04/2014; 2(1):38. DOI:10.1186/2051-5960-2-38
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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 · 4.28 Impact Factor
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    • "Nakagomi et al. (2008) provided evidence for such an association, and reported that Golgi fragmentation and dispersal precede neuronal cell death following oxidative/nitrosative insults, excitotoxins, and ER stress. Moreover, a dominant-negative fragment of a Golgiassociated protein, GRASP65, blocks Golgi fragmentation and cell death (Nakagomi et al., 2008 "
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    ABSTRACT: Huntington's disease (HD) is an autosomal-dominant neurodegenerative disease caused by the expansion of polyglutamine repeats in the gene for huntingtin (Htt). In HD, the corpus striatum selectively degenerates despite the uniform expression of mutant huntingtin (mHtt) throughout the brain and body. Striatal selectivity reflects the binding of the striatal-selective protein Rhes to mHtt to augment cytotoxicity, but molecular mechanisms underlying the toxicity have been elusive. Here, we report that the Golgi protein acyl-CoA binding domain containing 3 (ACBD3) mediates mHtt cytotoxicity via a Rhes/mHtt/ACBD3 complex. ACBD3 levels are markedly elevated in the striatum of HD patients, in a striatal cell line harboring polyglutamine repeats, and in the brains of HD mice. Moreover, ACBD3 deletion abolishes HD neurotoxicity, which is increased by ACBD3 overexpression. Enhanced levels of ACBD3 elicited by endoplasmic reticulum, mitochondrial, and Golgi stresses may account for HD-associated augmentation of ACBD3 and neurodegeneration.
    Cell Reports 09/2013; 4(5). DOI:10.1016/j.celrep.2013.08.001 · 8.36 Impact Factor
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