Comment on “A Neurotoxic Phosphoform of Elk-1 Associates with Inclusions from Multiple Neurodegenerative Diseases” by Sharma et al

The data from Sharma et al is suggestive of a pro cell death role of Elk1 that has been phosphorylated at T417.  Antibodies against p-T417 Elk1 identify inclusions in a variety of neurodegenerative diseases, including PD, but interestingly these inclusions are cytoplasmic.  This is perhaps surprising as Elk1 is a transcription factor and one of the outputs of the MAPK signaling pathways, but like many nuclear proteins Elk1 is also thought to play roles outside the nucleus in post-mitototic cells such as neurons.  Therefore, p-T417 Elk1 may be a general marker of the neurodegenerative process.

Personally, I find it difficult to interpret markers that come up in all neurodegenerative diseases.  On the one hand they are probably interesting as the might represent late events that could be interfered with to prevent many types of neuronal damage.  Assuming that p-T417 plays a causal role in neurodegeneration and is not simply a bystander, then this is quite exciting.  On the other hand, generic events probably don’t tell us much about the underlying causation of any one specific disease (unlike gene mutations, which tend to be more specific) and they could be interpreted as non-specific responses of a neuron that is committed to dying.  Figuring out whether elk-1 plays a causal role or is a bystander is complicated.  I would point to tau as an example, that can be a required player in some diseases (FTDP-17, where mutations can be found) or as a risk factor in others (PD, CBD and AD) where the pathology of these conditions is quite diverse.

One way of determining if Elk1 is sufficient to cause neurodegeneration is to express it in an experimental setting and this is one of the most exciting aspects of the Sharma et al paper.  The phototransduction method they use for figure 1 of their study allows the localized introduction of a gene into the dendritic region of a neuron.  One could imagine this being used for other genes that are involved in PD, such as a-synuclein or LRRK2.  This allowed the authors to show that T417 is required for the toxic effects of Elk1, albeit in a culture model.  There are some logical extensions to this observation that might allow mechanism to explored more; does a T417D/E phosphomimic show enhanced cell death?  What is the kinase involved in neurons?  However, technically, being able to introduce constructs in such a localized fashion is very impressive and allows these kinds of questions to be answered in future experiments.