Implication of a sumoylated c-terminal fragment of the astroglial glutamate transporter, EAAT2 in the non-cell autonomous mechanisms of amyotrophic lateral sclerosis pathogenesis

Emily Foran, Thomas Jefferson University

Abstract

Amyotrophic Lateral Sclerosis is an adult onset neurodegenerative disorders with a media age of onset of 55 year of age and a rapid degeneration leading to death within five years of diagnosis. There is no cure for ALS and only one FDA approved drug treatment, Rilutek™, with limited efficacy. Clinical characteristics of ALS derive from the dysfunction and death of the upper and lower motor neurons of the brainstem, spinal cord and periphery. Studies have shown that there is substantial involvement of cell types other than the motor neuron in ALS. It has been shown that the presence of healthy and functional astrocytes surrounding diseased motor neurons ameliorates disease progression and increase survival duration in an animal model of ALS. Within the CNS astrocytes are vital for glutamate homeostasis, in particular for the rapid and consistent removal of released glutamate from excitatory synapses. Studies have shown that in the course of ALS there are protein and functional decreases and abnormalities to the primary astrocytic glutamate transporter, EAAT2. We present here evidence of a novel and unique pathway of EAAT2 pathophysiology, which leads to astrocytic dysfunction and motor neuron cell death. Moreover, we show that EAAT2 is physiologically sumoylated by the small ubiquitin-related modifier 1, SUMO1. In ALS, EAAT2-SUMO1 becomes vulnerable to caspase-3 cleavage leading to the creation and accumulation of a sumoylated cytosolic free c-terminal fragment of EAAT2 (CTE-SUMO1). CTE-SUMO1 preferentially localizes to the nucleus of astrocytes, where it associates with PML nuclear bodies altering the genetic profile of the astrocytes. Ntn-1, a gene encoding a known axon guidance soluble protein, Netrin-1, is dramatically up-regulated and released by astrocytes expressing CTE-SUMO1. We have shown here that Netrin-1 is able to cause motor neuron cell death.

Subject Area

Neurosciences

Recommended Citation

Foran, Emily, "Implication of a sumoylated c-terminal fragment of the astroglial glutamate transporter, EAAT2 in the non-cell autonomous mechanisms of amyotrophic lateral sclerosis pathogenesis" (2013). ETD Collection for Thomas Jefferson University. AAI3598582.
https://jdc.jefferson.edu/dissertations/AAI3598582

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