A neurotoxic phosphoform of Elk-1 associates with inclusions from multiple neurodegenerative diseases Journal Article


Authors: Sharma, A.; Callahan, L. M.; Sul, J. Y.; Kim, T. K.; Barrett, L.; Kim, M.; Powers, J. M.; Federoff, H.; Eberwine, J.
Article Title: A neurotoxic phosphoform of Elk-1 associates with inclusions from multiple neurodegenerative diseases
Abstract: Neurodegenerative diseases are characterized by a number of features including the formation of inclusions, early synaptic degeneration and the selective loss of neurons. Molecules serving as links between these shared features have yet to be identified. Identifying candidates within the diseased microenvironment will open up novel avenues for therapeutic intervention. The transcription factor Elk-1 resides within multiple brain areas both in nuclear and extranuclear neuronal compartments. Interestingly, its de novo expression within a single dendrite initiates neuronal death. Given this novel regionalized function, we assessed whether extranuclear Elk-1 and/or phospho-Elk-1 (pElk-1) protein might be associated with a spectrum of human neurodegenerative disease cases including Lewy body Disease (e.g. Parkinson's), Alzheimer's disease, and Huntington's Disease. We first determined the importance of Elk-1 post-translational modifications on its ability to initiate regionalized cell death. We next screened human cases from three major neurodegenerative diseases to look for remarkable levels of Elk-1 and/or pElk-1 protein as well as their association with inclusions characteristic of these diseases. We compared our findings to age-matched control cases. We find that the ability of Elk-1 to initiate regionalized neuronal death depends on a specific phosphosite, T417. Furthermore, we find that T417+ Elk-1 uniquely associates with several types of inclusions present in cases of human Lewy body Disease, Alzheimer's disease, and Huntington's Disease. These results suggest a molecular link between the presence of inclusions and neuronal loss that is shared across a spectrum of neurodegenerative disease. © 2010 Sharma et al.
Keywords: immunohistochemistry; human tissue; protein expression; aged; aged, 80 and over; middle aged; genetics; nonhuman; neurotoxicity; animal cell; animal; cytology; metabolism; animals; animal tissue; cells, cultured; cell compartmentalization; confocal microscopy; microscopy, confocal; neurons; pathology; transfection; phosphorylation; protein processing; genetic transfection; cell culture; rat; binding site; mutagenesis, site-directed; threonine; binding sites; rats; cell nucleus; parkinson disease; site directed mutagenesis; nerve cell; brain region; alzheimer disease; degenerative disease; dendrite; neurodegenerative diseases; nerve cell necrosis; transcription factor elk 1; cell inclusion; huntington chorea; lewy body; diffuse lewy body disease; ets-domain protein elk-1; huntington disease; inclusion bodies; lewy body disease
Journal Title: PLoS ONE
Volume: 5
Issue: 2
ISSN: 1932-6203
Publisher: Public Library of Science  
Date Published: 2010-02-01
Start Page: e9002
Language: English
DOI: 10.1371/journal.pone.0009002
PUBMED: 20126313
PROVIDER: scopus
PMCID: PMC2814869
DOI/URL:
Notes: --- - "Export Date: 20 April 2011" - "Article No. e9002" - "Source: Scopus"
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