A Script for a Requiem - The Mechanism of Excitotoxicity

In stroke and a range of chronic neurodegenerative diseases, neurodegeneration results from the accumulation and exaggerated action of Glutamate (Glu). In these conditions, Glu accumulates in synapses because Glu Transporters (GluTs) can not function when brain cells do not have enough energy. The overstimulation of post synaptic Glu receptors triggers a neurodegenerative cascade called excitotoxicity. Currently there is no therapy for excitotoxicity, and a large group of recent clinical trials that were based on our current understanding of excitotoxicity ended with disappointment. These failures indicate that in spite of the urge to go directly to clinical and translational research, public health might be better served in the long run if we expand the basis of our understanding of the cellular pathways that lead to excitotoxic neurodegeneration.

We take advantage of the powerful tools available in C. elegans research to perform a genetic screen that is unbiased by previous understanding. We have recently produced a unique and reliable C. elegans model for excitotoxic neurodegeneration by knocking out GluTs in a sensitized background, resulting in necrosis of neurons postsynaptic to glutamatergic connections. The excitotoxic necrosis depends of the Ca2+ -permeable AMPA receptors expressed in these synapses. We now screen for genes that are specifically involved in neurodegeneration by methodically looking for interruptions in other genes that can block, reduce or enhance excitotoxic neurodegeneration.

We have recently identified DAPK, Ca2+ -sensitive kinase and a key regulator of cell death cascades, as an important mediator of excitotoxic necrosis in C. elegans. However, its activity is not mediated by a range of previously proposed mechanisms, and instead depends on the propyl isomerase Pin1. We are currently following the degenerative pathway to determine how DAPK is able to cooperate with Pin1 to produce excitotoxic necrosis.

This project is uniquely poised to provide a whole-organism view of Glu balance and to pin-down new genetic means to stop/slow excitotoxicity, without the bias of prior dogmas, addressing a major health concern of the general population with a fresh and promising approach.