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.
Subject(s)
Amyotrophic Lateral Sclerosis/genetics , Membrane Proteins/metabolism , MicroRNAs/genetics , Motor Neurons/physiology , PTEN Phosphohydrolase/metabolism , Adenoviridae , Animals , Cell Line, Tumor , Extremities/innervation , Humans , Induced Pluripotent Stem Cells , Injections, Spinal , Membrane Proteins/genetics , Mice , Mutation/genetics , Neuroprotection , PTEN Phosphohydrolase/genetics , RNA, Long Noncoding , Superoxide Dismutase-1/geneticsABSTRACT
Motor neurons (MNs) are unique because they project their axons outside of the CNS to innervate the peripheral muscles. Limb-innervating lateral motor column MNs (LMC-MNs) travel substantially to innervate distal limb mesenchyme. How LMC-MNs fine-tune the balance between survival and apoptosis while wiring the sensorimotor circuit en route remains unclear. Here, we show that the mir-17â¼92 cluster is enriched in embryonic stem cell (ESC)-derived LMC-MNs and that conditional mir-17â¼92 deletion in MNs results in the death of LMC-MNs in vitro and in vivo. mir-17â¼92 overexpression rescues MNs from apoptosis, which occurs spontaneously during embryonic development. PTEN is a primary target of mir-17â¼92 responsible for LMC-MN degeneration. Additionally, mir-17â¼92 directly targets components of E3 ubiquitin ligases, affecting PTEN subcellular localization through monoubiquitination. This miRNA-mediated regulation modulates both target expression and target subcellular localization, providing LMC-MNs with an intricate defensive mechanism that controls their survival.
