RESUMO
Amyotrophic lateral sclerosis (ALS) is an adult-onset incurable motor neuron (MN) disease. The reasons for selective MN vulnerability in ALS are unknown. Axonal pathology is among the earliest signs of ALS. We searched for novel modulatory genes in human MN axon shortening affected by TARDBP mutations. In transcriptome analysis of RNA present in the axon compartment of human-derived induced pluripotent stem cell (iPSC)-derived MNs, PHOX2B (paired-like homeobox protein 2B) showed lower expression in TARDBP mutant axons, which was consistent with axon qPCR and in situ hybridization. PHOX2B mRNA stability was reduced in TARDBP mutant MNs. Furthermore, PHOX2B knockdown reduced neurite length in human MNs. Finally, phox2b knockdown in zebrafish induced short spinal axons and impaired escape response. PHOX2B is known to be highly express in other types of neurons maintained after ALS progression. Collectively, TARDBP mutations induced loss of axonal resilience, which is an important ALS-related phenotype mediated by PHOX2B downregulation.
Assuntos
Esclerose Lateral Amiotrófica/metabolismo , Axônios/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Homeodomínio/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Neurônios Motores/metabolismo , Fatores de Transcrição/metabolismo , Peixe-Zebra/metabolismo , Esclerose Lateral Amiotrófica/genética , Animais , Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes/métodos , Proteínas de Homeodomínio/genética , Humanos , Mutação , Fenótipo , Fatores de Transcrição/genética , TranscriptomaRESUMO
C60- and C100-dolichols were synthesized. A Z-selective Wittig reaction was achieved with high selectivity in a microflow system to realize the scalable supply of the Z-isoprene unit. An isoprene chain was efficiently elongated by an SN2-type coupling between allyl sulfone and allyl chloride using t-BuOK. These key reactions enabled the efficient syntheses of dolichols. This study will pave the way for the functional studies of dolichols.
