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Altered astrocytic expression of TDP-43 does not influence motor neuron survival.
Haidet-Phillips, Amanda M; Gross, Sarah K; Williams, Timothy; Tuteja, Alisha; Sherman, Alex; Ko, Myungsung; Jeong, Yun H; Wong, Philip C; Maragakis, Nicholas J.
Afiliação
  • Haidet-Phillips AM; Department of Neurology, Johns Hopkins University School of Medicine, Rangos 248, 855 North Wolfe Street, Baltimore, MD 21205, USA.
Exp Neurol ; 250: 250-9, 2013 Dec.
Article em En | MEDLINE | ID: mdl-24120466
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Astrócitos / Proteínas de Ligação a DNA / Esclerose Lateral Amiotrófica / Neurônios Motores Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2013 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Astrócitos / Proteínas de Ligação a DNA / Esclerose Lateral Amiotrófica / Neurônios Motores Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2013 Tipo de documento: Article