Mir-17â¼92 Confers Motor Neuron Subtype Differential Resistance to ALS-Associated Degeneration.
Cell Stem Cell
; 25(2): 193-209.e7, 2019 08 01.
Article
en En
| MEDLINE
| ID: mdl-31155482
ABSTRACT
Progressive degeneration of motor neurons (MNs) is the hallmark of amyotrophic lateral sclerosis (ALS). Limb-innervating lateral motor column MNs (LMC-MNs) seem to be particularly vulnerable and are among the first MNs affected in ALS. Here, we report association of this differential susceptibility with reduced expression of the mir-17â¼92 cluster in LMC-MNs prior to disease onset. Reduced mir-17â¼92 is accompanied by elevated nuclear PTEN in spinal MNs of presymptomatic SOD1G93A mice. Selective dysregulation of the mir-17â¼92/nuclear PTEN axis in degenerating SOD1G93A LMC-MNs was confirmed in a double-transgenic embryonic stem cell system and recapitulated in human SOD1+/L144F-induced pluripotent stem cell (iPSC)-derived MNs. We further show that overexpression of mir-17â¼92 significantly rescues human SOD1+/L144F MNs, and intrathecal delivery of adeno-associated virus (AAV)9-mir-17â¼92 improves motor deficits and survival in SOD1G93A mice. Thus, mir-17â¼92 may have value as a prognostic marker of MN degeneration and is a candidate therapeutic target in SOD1-linked ALS. VIDEO ABSTRACT.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
MicroARNs
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Fosfohidrolasa PTEN
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Esclerosis Amiotrófica Lateral
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Proteínas de la Membrana
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Neuronas Motoras
Tipo de estudio:
Risk_factors_studies
Límite:
Animals
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Humans
Idioma:
En
Revista:
Cell Stem Cell
Año:
2019
Tipo del documento:
Article