RESUMEN
Huntington's disease is caused by an expansion of CAG repeats in exon 1 of the huntingtin gene encoding an extended PolyQ tract within the Huntingtin protein (mHtt). This expansion results in selective degeneration of striatal medium spiny projection neurons in the basal ganglia. The mutation causes abnormalities during neurodevelopment in human and mouse models. Here, we report that mHtt/PolyQ aggregates inhibit the cell cycle in the Drosophila brain during development. PolyQ aggregates disrupt the nuclear pore complexes of the cells preventing the translocation of cell cycle proteins such as Cyclin E, E2F and PCNA from cytoplasm to the nucleus, thus affecting cell cycle progression. PolyQ aggregates also disrupt the nuclear pore complex and nuclear import in mHtt expressing mammalian CAD neurons. PolyQ toxicity and cell cycle defects can be restored by enhancing RanGAP-mediated nuclear import, suggesting a potential therapeutic approach for this disease.
RESUMEN
This is a case of a patient with history of ear surgery who visited ENT outdoor, for continuous vertigo which used to get aggravated with loud noise, associated with hearing loss, persistent sensations of right-sided aural fullness/pressure and otalgia for last 2 years. He had history of tympanoplasty with ossiculoplasty using a TORP. On exploration under local anesthesia there was a displaced prosthesis into inner ear, upon removal of which symptoms and severity subsided exponentially.
RESUMEN
Disruption of the nuclear pore complex (NPC) and nucleocytoplasmic transport (NCT) have been implicated in the pathogenesis of neurodegenerative diseases. A GGGGCC hexanucleotide repeat expansion (HRE) in an intron of the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia, but the mechanism by which the HRE disrupts NCT is incompletely understood. We find that expression of GGGGCC repeats in Drosophila neurons induces proteasome-mediated degradation of select nucleoporins of the NPC. This process requires the Vps4 ATPase and the endosomal-sorting complex required for transport complex-III (ESCRT-III), as knockdown of ESCRT-III/Vps4 genes rescues nucleoporin levels, normalizes NCT, and suppresses GGGGCC-mediated neurodegeneration. GGGGCC expression upregulates nuclear ESCRT-III/Vps4 expression, and expansion microscopy demonstrates that the nucleoporins are translocated into the cytoplasm before undergoing proteasome-mediated degradation. These findings demonstrate a mechanism for nucleoporin degradation and NPC dysfunction in neurodegenerative disease.
Asunto(s)
Esclerosis Amiotrófica Lateral , Proteínas de Drosophila , Demencia Frontotemporal , Enfermedades Neurodegenerativas , Adenosina Trifosfatasas/metabolismo , Esclerosis Amiotrófica Lateral/metabolismo , Animales , Proteína C9orf72/genética , Expansión de las Repeticiones de ADN , Drosophila/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Complejos de Clasificación Endosomal Requeridos para el Transporte/genética , Complejos de Clasificación Endosomal Requeridos para el Transporte/metabolismo , Demencia Frontotemporal/metabolismo , Enfermedades Neurodegenerativas/genética , Proteínas de Complejo Poro Nuclear/genética , Proteínas de Complejo Poro Nuclear/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Regulación hacia Arriba/genéticaRESUMEN
Amyotrophic lateral sclerosis (ALS) is a devastating disorder in which motor neurons degenerate, the causes of which remain unclear. In particular, the basis for selective vulnerability of spinal motor neurons (sMNs) and resistance of ocular motor neurons to degeneration in ALS has yet to be elucidated. Here, we applied comparative multi-omics analysis of human induced pluripotent stem cell-derived sMNs and ocular motor neurons to identify shared metabolic perturbations in inherited and sporadic ALS sMNs, revealing dysregulation in lipid metabolism and its related genes. Targeted metabolomics studies confirmed such findings in sMNs of 17 ALS (SOD1, C9ORF72, TDP43 (TARDBP) and sporadic) human induced pluripotent stem cell lines, identifying elevated levels of arachidonic acid. Pharmacological reduction of arachidonic acid levels was sufficient to reverse ALS-related phenotypes in both human sMNs and in vivo in Drosophila and SOD1G93A mouse models. Collectively, these findings pinpoint a catalytic step of lipid metabolism as a potential therapeutic target for ALS.
Asunto(s)
Esclerosis Amiotrófica Lateral , Células Madre Pluripotentes Inducidas , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/metabolismo , Animales , Modelos Animales de Enfermedad , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Metabolismo de los Lípidos/genética , Ratones , Ratones Transgénicos , Neuronas Motoras/fisiología , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa-1/genéticaRESUMEN
Expansion of CAG repeats in certain genes has long been known to be associated with neurodegenerastion, but the quest to identity the underlying mechanisms is still on. Here, we analyzed the role of Yorkie, the coactivator of the Hippo pathway, and provide evidence to state that it is a robust genetic modifier of polyglutamine (PolyQ)-mediated neurodegeneration. Yorkie reduces the pathogenicity of inclusion bodies in the cell by activating cyclin E and bantam, rather than by preventing apoptosis through DIAP1. PolyQ aggregates inhibit Yorkie functioning at the protein, rather than the transcript level, and this is probably accomplished by the interaction between PolyQ and Yorkie. We show that PolyQ aggregates upregulate expression of antimicrobial peptides (AMPs) and Yorkie negatively regulates immune deficiency (IMD) and Toll pathways through relish and cactus, respectively, thus reducing AMPs and mitigating PolyQ affects. These studies strongly suggest a novel mechanism of suppression of PolyQ-mediated neurotoxicity by Yorkie through multiple channels.