Mir-17∼92 Confers Motor Neuron Subtype Differential Resistance to ALS-Associated Degeneration

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-17 similar to 92 cluster in LMC-MNs prior to disease onset. Reduced mir-17 similar to 92 is accompanied by elevated nuclear PTEN in spinal MNs of presymptomatic SOD1(G93A) mice. Selective dysregulation of the mir-17 similar to 92/nuclear PTEN axis in degenerating SOD1(G93A) 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-17 similar to 92 significantly rescues human SOD1(+/L144F) MNs, and intrathecal delivery of adeno-associated virus (AAV)9-mir-17 similar to 92 improves motor deficits and survival in SOD1(G93A) mice. Thus, mir-17 similar to 92 may have value as a prognostic marker of MN degeneration and is a candidate therapeutic target in SOD1-linked ALS.