ENAGenomicsMultiomicsNeurobiology, SISSA/ISAS (International School for Advanced Studies)https://www.ebi.ac.uk/ena/browser/view/PRJNA135111Mus musculusxref:PubMed:21769946Downregulation of expression and activity levels of the astroglial glutamate transporter EAAT2 is thought to be implicated in motor neuron excitotoxicity in amyotrophic lateral sclerosis (ALS). We previously reported that EAAT2 is cleaved by caspase-3 at the cytosolic C-terminus domain, impairing the transport activity and generating a proteolytic fragment found to be SUMO1 conjugated (CTE-SUMO1). We show here that this fragment accumulates in the nucleus of spinal cord astrocytes in vivo throughout the disease stages of the SOD1-G93A mouse model of ALS. In vitro expression in spinal cord astrocytes of the C-terminus peptide of EAAT2 (CTE), which was artificially fused to SUMO1 (CTE-SUMO1fus) to mimic the endogenous SUMOylation reaction, recapitulates the nuclear accumulation of the fragment seen in vivo and causes caspase-3 activation and axonal growth impairment in motor neuron-derived NSC-34 cells and primary motor neurons co-cultured with CTE-SUMO1fus-expressing spinal cord astrocytes. This indicates that CTE-SUMO1fus could trigger non-cell autonomous mechanisms of neurodegeneration. Prolonged nuclear accumulation of CTE-SUMO1fus in astrocytes leads to their degeneration, although the time frame of the cell-autonomous toxicity is longer than the one for the indirect toxic effect on motor neurons. As more evidence on the implication of SUMO substrates in neurodegenerative diseases emerges, our observations strongly suggest that the nuclear accumulation in spinal cord astrocytes of a SUMOylated proteolytic fragment of the astroglial glutamate transporter EAAT2 could take part to the pathogenesis of ALS and suggest a novel, unconventional role for EAAT2 in motor neuron degeneration in ALS. Overall design: Comparison is made between the toxic fragment (SUMO) and the same fragment without lysines that can be sumo-ylated (CTE). Four replicates have been performed for each sample group.ENAglutamic acid, Lou Gehrig disease, Dalpha1, Aluminum, glutamic acid dianion, DmelCG5610, 2-aminopentanedioate, Glt, Gehrigs Disease, Sclerosis, Glu, Amyotrophic Lateral Sclerosis, IPOA, glutamate, Aluminum L Glutamate, motor neuron disease, GLT1, bulbar, 2-Aminoglutaric acid, Aluminum L-Glutamate, Lou Gehrig's disease, LOU GEHRIGS DIS, alpha1, Gehrig Disease, Glutamic acid, ALS (Amyotrophic Lateral Sclerosis), E, Motor neuron disease, Lou-Gehrigs, 2900019G14Rik, Acr96Aa, GEHRIGS DIS, Guam Form of Amyotrophic Lateral Sclerosis, alpha-like, Lateral Scleroses, glutamate(2-), genetic, Amyotrophic lateral sclerosis, SOD, Glutaminic acid, AI159670, constitutitional genetic, Lou Gehrig Disease, Potassium, homodimer, Bulbar motor neuron disease, Amyotrophic lateral sclerosis (disorder), Disease, hydrogen glutamate, ALS, dALS, amyotrophic lateral sclerosis, Guam Form, CG5610-PA, L-Glutamic Acid, MGLT1, familial, mKIAA4111, glutamate(1-), Parkinsonism/Dementia complex of Guam, Lou Gehrigs Disease, Lou Gehrig's Disease, ALs, als, Glutamate, Potassium Glutamate, Amyotrophic Lateral, Glutamic Acid, CG5610, Axon., ALS1, Glutaminsaeure, D Glutamate, nAcRs, L-Glutamate, L Glutamic Acid, Albs, LOU GEHRIG DIS, DL-Glutaminic acid, 2-aminopentanedioic acid, Motor Neuron Disease, Acr96A, Gehrig's Disease, Dementia With Amyotrophic Lateral Sclerosis, AcrB, Lou-Gehrigs Disease, hSod1, AMYOTROPHIC SCLEROSIS, ALS - Amyotrophic lateral sclerosis, nAChR, nAcr96Aa, 1700091C19Rik, Eaat2, Amyotrophic, (D)-Isomer, L-Glutamic acid, glutamic acid monoanion, Glt-1, HEL-S-44, L Glutamate, MOTOR NEURON DIS AMYOTROPHIC LATERAL SCLEROSIS, 2-ammoniopentanedioate, D-Glutamate, inherited genetic, Charcot disease, hereditary, Amyotrophic Lateral Sclerosis With Dementia, Amyotrophic Lateral Sclerosis-Parkinsonism/dementia Complex 1, DL-Glutamic acid, GLT-1Mus musculus, Laboratory Mice., House, Mus, Laboratory, Swiss, Mus domesticus, mouse, Mus musculus domesticus, Swiss Mouse, mouse <Mus musculus>, Mouse, House Mice, Swiss Mice, house mouse, Mice, Laboratory Mouse, House Mouse, mice C57BL/6xCBA/CaJ hybrid, domesticus, Mus muscarisfalseMus musculusA SUMOylated C-terminus fragment of glutamate transporter EAAT2 linked to inherited ALS mediates motor axon impairment2025-09-242014-02-11PRJNA135111GSE260701009021769946