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Dynein and dynactin components modulate neurodegeneration induced by excitotoxicity
Author(s) -
Fujiwara Takeshi,
Morimoto Koji,
Kakita Akiyoshi,
Takahashi Hitoshi
Publication year - 2012
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2012.07746.x
Subject(s) - excitotoxicity , neurodegeneration , dynactin , neuroscience , neuroprotection , huntingtin , glutamate receptor , biology , microbiology and biotechnology , axon , neurotoxicity , dynein , chemistry , microtubule , medicine , biochemistry , pathology , mutant , disease , receptor , organic chemistry , toxicity , gene
J. Neurochem. (2012) 122 , 162–174. Abstract Glutamate excitotoxicity causes neuronal dysfunction and degeneration. It is implicated in chronic disorders, including Alzheimer’s disease, and in acute CNS insults such as ischemia. These disorders share prominent morphological features, including axon degeneration and cell body death. However, the molecular mechanism underlying excitotoxicity‐induced neurodegeneration remains poorly understood. A key molecular feature of neurodegeneration is deficits in microtubule‐based cargo transport that plays a pivotal role in maintaining the balance of survival and stress signaling in the axon. We developed an excitotoxicity‐induced neurodegeneration system in primary neuronal cultures. We find that excitotoxicity generates a C‐terminal truncated form of p150Glued, a major component of the dynactin complex, which exacerbates axon degeneration. This p150Glued truncated form was identified in brain tissues of patients with Alzheimer’s disease. Overexpression of wild‐type (WT) dynein intermediate chain (DIC), a dynein component that interacts with p150Glued and links dynein and dynactin complexes, DIC (S84D) mutant, and WT p150Glued suppressed axon degeneration. These modulating effects of p150Glued and DIC on excitotoxicity‐induced axon degeneration are also observed in apoptosis and cell body death. Thus, our findings identify retrograde transport proteins, p150Glued and DIC, as novel modulators of neurodegeneration induced by glutamate excitotoxicity.