Showing papers by "Srinivasa Subramaniam published in 2022"
TL;DR: It is shown that SUMO deletion in a humanized mouse HD model depletes mHTT and prevents brain shrinkage and behavioral abnormalities, and that blocking SUMO may ameliorate HD pathogenesis by regulating autophagy activities.
Abstract: Significance SUMO protein can decorate other proteins via a process called SUMOylation that can regulate toxicity of proteins linked to neurodegenerative diseases. The mutant huntingtin (mHTT) protein in Huntington disease (HD) degenerates nerve cells, and SUMOylation of mHTT makes it more soluble and more toxic to the nerve cells. Here, we show that SUMO deletion in a humanized mouse HD model depletes mHTT and prevents brain shrinkage and behavioral abnormalities. SUMO deletion blocked inflammation and enhanced autophagy, a beneficial cellular degradation pathway. Importantly, ginkgolic acid (GA), a widely used plant supplement that can inhibit SUMOylation, activates autophagy and promotes the degradation of mHTT in human HD cells. Thus, our study indicates GA and analogs might be therapeutically beneficial to HD patients. The CAG expansion of huntingtin (mHTT) associated with Huntington disease (HD) is a ubiquitously expressed gene, yet it prominently damages the striatum and cortex, followed by widespread peripheral defects as the disease progresses. However, the underlying mechanisms of neuronal vulnerability are unclear. Previous studies have shown that SUMO1 (small ubiquitin-like modifier-1) modification of mHtt promotes cellular toxicity, but the in vivo role and functions of SUMO1 in HD pathogenesis are unclear. Here, we report that SUMO1 deletion in Q175DN HD-het knockin mice (HD mice) prevented age-dependent HD-like motor and neurological impairments and suppressed the striatal atrophy and inflammatory response. SUMO1 deletion caused a drastic reduction in soluble mHtt levels and nuclear and extracellular mHtt inclusions while increasing cytoplasmic mHtt inclusions in the striatum of HD mice. SUMO1 deletion promoted autophagic activity, characterized by augmented interactions between mHtt inclusions and a lysosomal marker (LAMP1), increased LC3B- and LAMP1 interaction, and decreased interaction of sequestosome-1 (p62) and LAMP1 in DARPP-32–positive medium spiny neurons in HD mice. Depletion of SUMO1 in an HD cell model also diminished the mHtt levels and enhanced autophagy flux. In addition, the SUMOylation inhibitor ginkgolic acid strongly enhanced autophagy and diminished mHTT levels in human HD fibroblasts. These results indicate that SUMO is a critical therapeutic target in HD and that blocking SUMO may ameliorate HD pathogenesis by regulating autophagy activities.
13 citations
TL;DR: The results indicate RasGRP1 may mediate risk for SCZ by involving DLPFC and peripheral blood, thus encouraging further studies to explore its possible role as a biomarker of the disease and/or a target for new medication.
Abstract: Schizophrenia (SCZ) is a polygenic severe mental illness. Genome-wide association studies (GWAS) have detected genomic variants associated with this psychiatric disorder and pathway analyses have indicated immune system and dopamine signaling as core components of risk in dorsolateral-prefrontal cortex (DLPFC) and hippocampus, but the mechanistic links remain unknown. The RasGRP1 gene, encoding for a guanine nucleotide exchange factor, is implicated in dopamine signaling and immune response. RasGRP1 has been identified as a candidate risk gene for SCZ and autoimmune disease, therefore representing a possible point of convergence between mechanisms involving the nervous and the immune system. Here, we investigated RasGRP1 mRNA and protein expression in post-mortem DLPFC and hippocampus of SCZ patients and healthy controls, along with RasGRP1 protein content in the serum of an independent cohort of SCZ patients and control subjects. Differences in RasGRP1 expression between SCZ patients and controls were detected both in DLPFC and peripheral blood of samples analyzed. Our results indicate RasGRP1 may mediate risk for SCZ by involving DLPFC and peripheral blood, thus encouraging further studies to explore its possible role as a biomarker of the disease and/or a target for new medication.
2 citations
30 Aug 2022
TL;DR: In this paper , the authors found that the mHTT expression initially restricted in the striatum later spread to the cortical regions in mouse brains, indicating a new transmission route for the Rhes protein to the brain.
Abstract: The CAG/CAA expansion encoding polyQ huntingtin (mutant huntingtin [mHTT]) causes Huntington's disease (HD), which is characterized by atrophy and loss of striatal medium spiny neurons (MSNs), which are preceded by neuropathological alterations in the cortex. Previous studies have shown that mHTT can spread in the brain, but the mechanisms involved in the stereotyped degeneration and dysfunction of the neurons from the striatum to the cortex remain unclear. In this study, we found that the mHTT expression initially restricted in the striatum later spread to the cortical regions in mouse brains. Such transmission was diminished in mice that lacked the striatal-enriched protein Ras-homolog enriched in the striatum (Rhes). Rhes restricted to MSNs was also found in the cortical layers of the brain, indicating a new transmission route for the Rhes protein to the brain. Mechanistically, Rhes promotes such transmission via a direct cell-to-cell contact mediated by tunneling nanotubes (TNTs), the membranous protrusions that enable the transfer of mHTT, Rhes, and other vesicular cargoes. These transmission patterns suggest that Rhes and mHTT are likely co-transported in the brain using TNT-like cell-to-cell contacts. On the basis of these new results, a perspective is presented in this review: Rhes may ignite the mHTT transmission from the striatum that may coincide with HD onset and disease progression through an anatomically connected striato-cortical retrograde route.
TL;DR: Rhes may ignite the mHTT transmission from the striatum that may coincide with HD onset and disease progression through an anatomically connected striato-cortical retrograde route, and transmission patterns suggest that Rhes and m HTT are likely co-transported in the brain using TNT-like cell-to-cell contacts.
Abstract: The CAG/CAA expansion encoding polyQ huntingtin (mutant huntingtin [mHTT]) causes Huntington’s disease (HD), which is characterized by atrophy and loss of striatal medium spiny neurons (MSNs), which are preceded by neuropathological alterations in the cortex. Previous studies have shown that mHTT can spread in the brain, but the mechanisms involved in the stereotyped degeneration and dysfunction of the neurons from the striatum to the cortex remain unclear. In this study, we found that the mHTT expression initially restricted in the striatum later spread to the cortical regions in mouse brains. Such transmission was diminished in mice that lacked the striatal-enriched protein Ras-homolog enriched in the striatum (Rhes). Rhes restricted to MSNs was also found in the cortical layers of the brain, indicating a new transmission route for the Rhes protein to the brain. Mechanistically, Rhes promotes such transmission via a direct cell-to-cell contact mediated by tunneling nanotubes (TNTs), the membranous protrusions that enable the transfer of mHTT, Rhes, and other vesicular cargoes. These transmission patterns suggest that Rhes and mHTT are likely co-transported in the brain using TNT-like cell-to-cell contacts. On the basis of these new results, a perspective is presented in this review: Rhes may ignite the mHTT transmission from the striatum that may coincide with HD onset and disease progression through an anatomically connected striato-cortical retrograde route.