Researchers from the University of Pennsylvania School of Medicine have identified the same toxic form of a protein known as Elk-1 within the abnormal inclusions found post-mortem in the brains of patients with Parkinson, Alzheimer, and Huntington diseases. Their results suggest that it is involved during a key stage of disease pathogenesis common to neurodegenerative diseases.
Their study is published in PloS One in a paper titled “A Neurotoxic Phosphoform of Elk-1 Associates with Inclusions from Multiple Neurodegenerative Diseases.”
It is known that the transcription factor Elk-1 resides in both nuclear and extranuclear neuronal compartments, but when present in nerve cell dendrites it can trigger neuronal death. In the current research, the team used phototransfection to focally introduce and express small amounts of Elk-1 mRNA into various compartments of a single primary hippocampal neuron.
Following phototransfection and expression of Elk-1 mRNA within dendrites, the majority of neurons undergo cell death that could be seen as early as 30 minutes to several hours later.
To investigate the possible link between normal or abnormal Elk-1 and neurodegenerative diseases, the researchers next determined the importance of Elk-1 post-translational modifications on its ability to initiate regionalized cell death. The resulting data suggested that the ability of Elk-1 to initiate regionalized neuronal death depended on a specific phosphosite T417.
They then screened human cases of Parkinson, Alzheimer, and Huntington diseases to look for abnormal levels of the Elk-1 and/or the modified phospho-modified Elk-1 protein, pElk1 as well as to assess their association with inclusions characteristic of these diseases. The results confirmed that pELK-1 was uniquely associated with the Lewy bodies in Parkinson disease, with the classic plaque, tangle, and thread morphologies in the Alzheimer brain, and the ubiquitin-containing inclusions in Huntington disease brain tissue.
“The co-localization of T417+ELK-1 with mutliple neuronal inclusions suggests a common mechanism of pathogenesis and neuronal loss among distinct neurodegenerative diseases,” the authors state.
“The linkage between Elk-1 and neurodegeneration raises an interesting set of issues regarding its potential as a therapeutic target. Its association with several types of inclusions suggests its involvement during an important stage of disease pathogenesis shared across a spectrum of neurodegenerative disease.”