Suppression of MAPK11 or HIPK3 reduces mutant Huntingtin levels in Huntington's disease models.

Most neurodegenerative disorders are associated with accumulation of disease-relevant proteins. Among them, Huntington disease (HD) is of particular interest because of its monogenetic nature. HD is mainly caused by cytotoxicity of the defective protein encoded by the mutant Huntingtin gene (HTT). Thus, lowering mutant HTT protein (mHTT) levels would be a promising treatment strategy for HD. Here we report two kinases HIPK3 and MAPK11 as positive modulators of mHTT levels both in cells and in vivo. Both kinases regulate mHTT via their kinase activities, suggesting that inhibiting these kinases may have therapeutic values. Interestingly, their effects on HTT levels are mHTT-dependent, providing a feedback mechanism in which mHTT enhances its own level thus contributing to mHTT accumulation and disease progression. Importantly, knockout of MAPK11 significantly rescues disease-relevant behavioral phenotypes in a knockin HD mouse model. Collectively, our data reveal new therapeutic entry points for HD and target-discovery approaches for similar diseases

Inhibiting MARSs reduces hyperhomocysteinemia‐associated neural tube and congenital heart defects

Hyperhomocysteinemia is a common metabolic disorder that imposes major adverse health consequences. Reducing homocysteine levels, however, is not always effective against hyperhomocysteinemia‐associated pathologies. Herein, we report the potential roles of methionyl‐tRNA synthetase (MARS)‐generated homocysteine signals in neural tube defects (NTDs) and congenital heart defects (CHDs). Increased copy numbers of MARS and/or MARS2 were detected in NTD and CHD patients. MARSs sense homocysteine and transmit its signal by inducing protein lysine (N)‐homocysteinylation. Here, we identified hundreds of novel N‐homocysteinylated proteins. N‐homocysteinylation of superoxide dismutases (SOD1/2) provided new mechanistic insights for homocysteine‐induced oxidative stress, apoptosis and Wnt signalling deregulation. Elevated MARS expression in developing and proliferating cells sensitizes them to the effects of homocysteine. Targeting MARSs using the homocysteine analogue acetyl homocysteine thioether (AHT) reversed MARS efficacy. AHT lowered NTD and CHD onsets in retinoic acid‐induced and hyperhomocysteinemia‐induced animal models without affecting homocysteine levels. We provide genetic and biochemical evidence to show that MARSs are previously overlooked genetic determinants and key pathological factors of hyperhomocysteinemia, and suggest that MARS inhibition represents an important medicinal approach for controlling hyperhomocysteinemia‐associated diseases

LSL-KrasG12D; LSL-Trp53R172H/+; Ink4flox/+; Ptf1/p48-Cre mice are an applicable model for locally invasive and metastatic pancreatic cancer.

Pancreatic cancer (PC) accumulates multiple genetic mutations, including activating KRAS mutations and inactivating TP53, SMAD4 and CDKN2A mutations, during progression. The combination of mutant KRAS with a single inactivating TP53, SMAD4 or CDKN2A mutation in genetically engineered mouse models (GEMMs) showed that these mutations exert different synergistic effects in PC. However, the effect of the combination of TP53, CDKN2A and KRAS mutations on the trajectory of PC progression is unknown. Here, we report a GEMM that harbors KRAS (KrasG12D), TP53 (Trp53R172H/+), CDKN2A (Ink4flox/+) and Ptf1/p48-Cre (KPIC) mutations. Histopathology showed that KPIC mice developed adenocarcinoma that strongly resembled the pathology of human PC, characterized by rich desmoplastic stroma and low microvascularity. The median survival of KPIC mice was longer than that of LSL-KrasG12D; Ink4flox/flox; Ptf1/p48-Cre mice (KIC) (89 vs 62 days) and shorter than that of KRAS (KrasG12D), TP53 (Trp53R172H/+) and Ptf1/p48-Cre (KPC) mice. Moreover, the neoplastic cells of KPIC mice were epithelial, highly proliferative tumor cells that exhibited ERK and MAPK pathway activation and high glucose uptake. Isolated neoplastic cells from spontaneous KPIC tumors showed all molecular profiles and cellular behaviors of spontaneous KPIC tumors, including epithelial-mesenchymal transition (EMT) under drug stress as well as tumorigenic, metastatic and invasive abilities in immunocompetent mice. Furthermore, orthotopic and metastatic tumors of KPIC cells almost recapitulated the pathology of spontaneous KPIC tumors. These data show that in addition to spontaneous KPIC tumors, KPIC cells are a valuable tool for preclinical studies of locally invasive and metastatic PC

Isolation and characterization of novel human short-chain dehydrogenase/reductase SCDR10B which is highly expressed in the brain and acts as hydroxysteroid dehydrogenase.

Hydroxysteroid dehydrogenase belongs to the subfamily of short-chain dehydrogenases/reductases (SDR), and 11-beta-hydroxysteroid dehydrogenase catalyzes the interconversion of inactive glucocorticoids (cortisone in human, dehydrocorticosterone in rodents) and active glucocorticoids (cortisol in human, corticosterone in rodents). We report here the cloning and characterization of a novel human SDR gene SCDR10B which encodes a protein with similarity to 11beta-hydroxysteroid dehydrogenase 1. SCDR10B was isolated from a human brain cDNA library, and was mapped to chromosome 19p13.3 by browsing the UCSC genomic database. It contains an ORF with a length of 858 bp, encoding a protein with a transmembrane helix and SDR domain. Its molecular mass and isoelectric point are predicted to be 30.8 kDa and 10.3 kDa, respectively. SCDR10B protein is highly conserved in mammals and fish. Phylogenetic tree analysis indicated that SCDR10B stands for a new subgroup in the 11beta-hydroxysteroid dehydrogenase family. Northern blot analysis showed that SCDR10B was highly expressed in brain, and a strong expression signal was detected in hippocampal neurons by immunohistochemical analysis. RT-PCR and immunohistochemical analysis showed that SCDR10B was up-regulated in lung-cancer cell lines and human lung cancer. SCDR10B can catalyze the dehydrogenation of cortisol in the presence of NADP(+), and therefore it is a hydroxysteroid dehydrogenase.</jats:p