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.

1 Follower
 · 
145 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The endoplasmic reticulum-lysosome-Golgi network plays an important role in Reelin glycosylation and its proteolytic processing. Golgi complex fragmentation is associated with the separation of Reelin from this network. Kainic acid (KA) is an excitotoxic agent commonly used to induce epilepsy in rodents. The relationship between KA-induced neuronal damage and Golgi complex fragmentation has not been investigated, leaving a major gap in our understanding of the molecular mechanism underlying the development of pathophysiology in epilepsy. We cultured primary rat cortical neurons eitherin ambient condition (control) or treated with a range of KA doses to reveal whether Golgi complex fragmentation impaired neuronal function. The half-life maximal inhibitory concentration (IC 50) value of KA was detected to be approximately 5 μM, whereby at these concentrations, KA impaired neuronal viability, which was closely associated with initial Golgi complex fragmentation and subsequent reduction in both the expression and glycosylation patterns of Reelin. These findings implicate that Golgi complex fragmentation and Reelin dysfunction are key contributors to neuronal cell death in the early stage of epilepsy pathophysiology, thereby representing as novel disease biomarkers, as well as potent therapeutic targets for epilepsy.
    Molecular Neurobiology 03/2015; DOI:10.1007/s12035-015-9126-1 · 5.29 Impact Factor
  • Source
  • [Show abstract] [Hide abstract]
    ABSTRACT: The onset and progression of Alzheimer's disease (AD) is closely associated with amyloid β (Aβ) peptide-induced cytotoxicity and abnormal protein transportation caused by breakdown of endoplasmic reticulum (ER)–Golgi apparatus trafficking network. Although the fragmentation of Golgi apparatus has been reported in AD human patients and various AD model animals, the molecular mechanisms causing the morpho-functional impairments of Golgi apparatus during AD progression remain poorly understood. Thus, we investigated the ultrastructure of Golgi apparatus and coat protein I (COPI) expression in β-amyloid precursor protein/presenilin-1 double transgenic mouse and Aβ-stimulated BV-2 cell as an AD model using cryo-immunogold electron microscopy. In the neurons of the hippocampus of transgenic mouse and BV-2 cell, the cisternae of Golgi stacks were fragmented in difference with that of wild type mouse and cells. In addition, we further showed the COPI depletion in Golgi apparatus, which demonstrated the impairment of molecular integrities of Golgi apparatus. Taken together, our results provide insights into the Golgi apparatus-involved morphopathology of AD and we suggest that the Golgi fragmentation is caused by the depletion of COPI affecting the intra-Golgi transport through stimulation and accumulation of Aβ during AD development.
    Animal cells and systems the official publication of the Zoological Society of Korea 01/2015; 19(1). DOI:10.1080/19768354.2014.984756 · 0.35 Impact Factor

Preview

Download
1 Download
Available from