Grant: Fellowship - Priority Announcement: Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disorder that primarily affects motor neurons in the cortex, brain stem, and spinal cord. The selective degeneration of these neurons leads to atrophy of skeletal muscle and, ultimately, to paralysis and death within 1-5 years. It is accepted that one of the crucial mechanisms of motor neurons' vulnerability in ALS is their increased susceptibility to excitotoxicity (the toxic effect of excitatory neurotransmitter glutamate on intracellular levels of calcium). This is mainly attributed to increased membrane localization of calcium-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. It was recently found that the pro-inflammatory cytokine, TNF-alpha, leads to calcium-permeable AMPA receptor trafficking, which underlies an important form of synaptic plasticity. In addition, TNF-alpha was shown to be elevated in ALS patients and it has been suggested that it is involved in the aetiology of the disease. However, the connection between TNF-alpha and AMPA receptor in the context of ALS pathology has never been thoroughly investigated. Therefore, understanding the mechanism by which TNF-alpha regulates AMPA receptor trafficking, and which AMPA receptor subunit contributes to synapse excitability, is central in understanding the pathophysiology of ALS and a large number of other neurological disorders. In my post-doctoral research I will use the mouse model of ALS, to investigate the hypothesis that progression of the disease results from increased release of cytokines from glia, leading to enhanced surface expression of calcium-permeable AMPA receptor and to excitotoxicity.