title: Altered astrocytic expression of TDP-43 does not influence motor neuron survival.
abstract: The role of glia as a contributing factor to motor neuron (MN) death in amyotrophic lateral sclerosis (ALS) is becoming increasingly appreciated. However, most studies implicating astrocytes have focused solely on models of ALS caused by superoxide dismutase 1 (SOD1) mutations. The goal of our study was to determine whether astrocytes contribute to wild-type MN death in the case of ALS caused by mutations in tar-DNA binding protein 43 (TDP-43). Since it is currently unknown how TDP-43 mutations cause disease, we derived astrocytes for study from both gain and loss of function mouse models of TDP-43. Astrocytes overexpressing mutant TDP-43(A315T) as well as astrocytes lacking TDP-43 were morphologically indistinguishable from wild-type astrocytes in vitro. Furthermore, astrocytes with these TDP-43 alterations did not cause the death of wild-type MNs in co-culture. To investigate the in vivo effects of TDP-43 alterations in astrocytes, glial-restricted precursors were transplanted to the wild-type rat spinal cord where they differentiated into astrocytes and interacted with host MNs. Astrocytes with TDP-43 alterations did not cause host wild-type MN damage although they were capable of engrafting and interacting with host MNs with the same efficiency as wild-type astrocytes. These data indicate that astrocytes do not adopt the same toxic phenotype as mutant SOD1 astrocytes when TDP-43 is mutated or expression levels are modified. Our study reinforces the heterogeneity in ALS disease mechanisms and highlights the potential for future screening subsets of ALS patients prior to treatment with cell type-directed therapies.
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Rangos 248, 855 North Wolfe Street, Baltimore, MD 21205, USA.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Haidet-Phillips
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Gross
authors.forename: Timothy
authors.initials: T
authors.lastname: Williams
authors.forename: Alisha
authors.initials: A
authors.lastname: Tuteja
authors.forename: Alex
authors.initials: A
authors.lastname: Sherman
authors.forename: Myungsung
authors.initials: M
authors.lastname: Ko
authors.forename: Yun H
authors.initials: YH
authors.lastname: Jeong
authors.forename: Philip C
authors.initials: PC
authors.lastname: Wong
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Maragakis
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D002470:Cell Survival; D018920:Coculture Techniques; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D004268:DNA-Binding Proteins; C578077:Tardbp protein, mouse
keywords: ALS; Amyotrophic lateral sclerosis; Cell autonomy; Glia; Stem cells