title: Expression of ALS-linked TDP-43 mutant in astrocytes causes non-cell-autonomous motor neuron death in rats.
abstract: Mutation of Tar DNA-binding protein 43 (TDP-43) is linked to amyotrophic lateral sclerosis. Although astrocytes have important roles in neuron function and survival, their potential contribution to TDP-43 pathogenesis is unclear. Here, we created novel lines of transgenic rats that express a mutant form of human TDP-43 (M337V substitution) restricted to astrocytes. Selective expression of mutant TDP-43 in astrocytes caused a progressive loss of motor neurons and the denervation atrophy of skeletal muscles, resulting in progressive paralysis. The spinal cord of transgenic rats also exhibited a progressive depletion of the astroglial glutamate transporters GLT-1 and GLAST. Astrocytic expression of mutant TDP-43 led to activation of astrocytes and microglia, with an induction of the neurotoxic factor Lcn2 in reactive astrocytes that was independent of TDP-43 expression. These results indicate that mutant TDP-43 in astrocytes is sufficient to cause non-cell-autonomous death of motor neurons. This motor neuron death likely involves deficiency in neuroprotective genes and induction of neurotoxic genes in astrocytes.
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Jianbin
authors.initials: J
authors.lastname: Tong
authors.forename: Cao
authors.initials: C
authors.lastname: Huang
authors.forename: Fangfang
authors.initials: F
authors.lastname: Bi
authors.forename: Qinxue
authors.initials: Q
authors.lastname: Wu
authors.forename: Bo
authors.initials: B
authors.lastname: Huang
authors.forename: Xionghao
authors.initials: X
authors.lastname: Liu
authors.forename: Fang
authors.initials: F
authors.lastname: Li
authors.forename: Hongxia
authors.initials: H
authors.lastname: Zhou
authors.forename: Xu-Gang
authors.initials: XG
authors.lastname: Xia
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology*; D001522:Behavior, Animal; D015153:Blotting, Western; D016923:Cell Death; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D027341:Excitatory Amino Acid Transporter 1 / Q000378:metabolism; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D000071068:Lipocalin-2; D054834:Lipocalins / Q000378:metabolism; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology*; D009121:Muscle Denervation; D009133:Muscular Atrophy / Q000209:etiology / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D010243:Paralysis / Q000209:etiology / Q000473:pathology; D051381:Rats; D055647:Rats, Transgenic; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology*
chemical_list: D004268:DNA-Binding Proteins; D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; C097278:Lcn2 protein, rat; D000071068:Lipocalin-2; D054834:Lipocalins; C493395:Slc1a2 protein, rat; C493392:Slc1a3 protein, rat