A novel HDAC6 inhibitor, CKD-504, is effective in treating preclinical models of huntington’s disease

Endan Li,Jiwoo Choi,Hye-Ri Sim,Jiyeon Kim,Jae Hyun Jun,Jangbeen Kyung,Nina Ha,Keun Ho Ryu,Seung Soo Chung,Hyun Sook Kim,Semi Kim,Sungsu Lee,Wongi Seol,송지환 생화학분자생물학회 2023 BMB Reports Vol.56 No.3

Huntington’s disease (HD) is a neurodegenerative disorder, ofwhich pathogenesis is caused by a polyglutamine expansion inthe amino-terminus of huntingtin gene that resulted in the aggregationof mutant HTT proteins. HD is characterized by progressivemotor dysfunction, cognitive impairment and neuropsychiatricdisturbances. Histone deacetylase 6 (HDAC6), amicrotubule-associated deacetylase, has been shown to inducetransport- and release-defect phenotypes in HD models, whilsttreatment with HDAC6 inhibitors ameliorates the phenotypiceffects of HD by increasing the levels of α-tubulin acetylation,as well as decreasing the accumulation of mutant huntingtin(mHTT) aggregates, suggesting HDAC6 inhibitor as a HD therapeutics. In this study, we employed in vitro neural stem cell(NSC) model and in vivo YAC128 transgenic (TG) mouse modelof HD to test the effect of a novel HDAC6 selective inhibitor,CKD-504, developed by Chong Kun Dang (CKD PharmaceuticalCorp., Korea). We found that treatment of CKD-504 increasedtubulin acetylation, microtubule stabilization, axonaltransport, and the decrease of mutant huntingtin protein invitro. From in vivo study, we observed CKD-504 improved thepathology of Huntington’s disease: alleviated behavioral deficits,increased axonal transport and number of neurons, restoredsynaptic function in corticostriatal (CS) circuit, reduced mHTTaccumulation, inflammation and tau hyperphosphorylation inYAC128 TG mouse model. These novel results highlight CKD-504as a potential therapeutic strategy in HD.

Insulin-Like Growth Factor-1 Inhibits 6-Hydroxydopamine-Mediated Endoplasmic Reticulum Stress-Induced Apoptosis via Regulation of Heme Oxygenase-1 and Nrf2 Expression in PC12 Cells

Kim, Yumi,Li, Endan,Park, Seungjoon Informa Healthcare 2012 International journal of neuroscience Vol.122 No.11

<P>Endoplasmic reticulum (ER) stress and oxidative stress appear to play a critical role in the progression of Parkinson's disease (PD). Insulin-like growth factor (IGF)-1, a 70-amino acid polypeptide trophic factor, acts as a potent neurotrophic, neurogenic, and neuroprotective/anti-apoptotic factor. In this study, we investigated the protective mechanisms of IGF-1 in rat pheochromocytoma PC12 cells exposed to the PD-related neurotoxin 6-hydroxydopamine (6-OHDA). The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) coordinates expression of genes required for free radical scavenging, detoxification of xenobiotics, and maintenance of redox potential. Exposure of cells to 6-OHDA resulted in an increase in ER-stress-induced apoptotic cell death, which was significantly reduced by treatment of cells with IGF-1. IGF-1 treatment significantly increased BiP and C/EBP homologous protein expression in 6-OHDA-treated cultures. IGF-1 protected cells from 6-OHDA-induced insult by inhibiting intracellular reactive oxygen species generation. Compared with vehicle-treated controls, the expression of Nrf2 and heme oxygenase-1 (HO-1) was increased in 6-OHDA-treated cells. IGF-1 significantly up-regulated HO-1 in cells exposed to 6-OHDA. These results suggest that IGF-1 augment cellular anti-oxidant defense mechanism, at least in part, through the up-regulation of HO-1 expression.</P>

Multiple signaling pathways mediate ghrelin-induced proliferation of hippocampal neural stem cells

Chung, Hyunju,Li, Endan,Kim, Yumi,Kim, Sehee,Park, Seungjoon Society for Endocrinology 2013 The Journal of endocrinology Vol.218 No.1

<P>Ghrelin, an endogenous ligand for the GH secretagogue receptor (GHS-R) receptor 1a (GHS-R1a), has been implicated in several physiologic processes involving the hippocampus. The aim of this study was to investigate the molecular mechanisms of ghrelin-stimulated neurogenesis using cultured adult rat hippocampal neural stem cells (NSCs). The expression of GHS-R1a was detected in hippocampal NSCs, as assessed by western blot analysis and immunocytochemistry. Ghrelin treatment increased the proliferation of cultured hippocampal NSCs assessed by BrdU incorporation. The exposure of cells to the receptor-specific antagonist <SMALL>d</SMALL>-Lys-3-GHRP-6 abolished the proliferative effect of ghrelin. By contrast, ghrelin showed no significant effect on cell differentiation. The expression of GHS-R1a was significantly increased by ghrelin treatment. The analysis of signaling pathways showed that ghrelin caused rapid activation of ERK1/2 and Akt, which were blocked by the GHS-R1a antagonist. In addition, ghrelin stimulated the phosphorylation of Akt downstream effectors, such as glycogen synthase kinase (GSK)-3β, mammalian target of rapamycin (mTOR), and p70<SUP>S6K</SUP>. The activation of STAT3 was also caused by ghrelin treatment. Furthermore, pretreatment of cells with specific inhibitors of MEK/ERK1/2, phosphatidylinositol-3-kinase (PI3K)/Akt, mTOR, and Jak2/STAT3 attenuated ghrelin-induced cell proliferation. Taken together, our results support a role for ghrelin in adult hippocampal neurogenesis and suggest the involvement of the ERK1/2, PI3K/Akt, and STAT3 signaling pathways in the mediation of the actions of ghrelin on neurogenesis. Our data also suggest that PI3K/Akt-mediated inactivation of GSK-3β and activation of mTOR/p70<SUP>S6K</SUP> contribute to the proliferative effect of ghrelin.</P>

Ghrelin Protects Spinal Cord Motoneurons Against Chronic Glutamate Excitotoxicity by Inhibiting Microglial Activation

Sungyoub Lee,Yumi Kim,Endan Li,Seungjoon Park 대한약리학회 2012 The Korean Journal of Physiology & Pharmacology Vol.16 No.1

Glutamate excitotoxicity is emerging as a contributor to degeneration of spinal cord motoneurons in amyotrophic lateral sclerosis (ALS). Recently, we have reported that ghrelin protects motoneurons against chronic glutamate excitotoxicity through the activation of extracellular signal-regulated kinase 1/2 and phosphatidylinositol-3-kinase/Akt/glycogen synthase kinase-3β pathways. Previous studies suggest that activated microglia actively participate in the pathogenesis of ALS motoneuron degeneration. However, it is still unknown whether ghrelin exerts its protective effect on motoneurons via inhibition of microglial activation. In this study, we investigate organotypic spinal cord cultures (OSCCs) exposed to threohydroxyaspartate (THA), as a model of excitotoxic motoneuron degeneration, to determine if ghrelin prevents microglial activation. Exposure of OSCCs to THA for 3 weeks produced typical motoneuron death, and treatment of ghrelin significantly attenuated THA-induced motoneuron loss, as previously reported. Ghrelin prevented THA-induced microglial activation in the spinal cord and the expression of pro-inflammatory cytokines tumor necrosis factor-α and interleukin-1β. Our data indicate that ghrelin may act as a survival factor for motoneurons by functioning as a microglia- deactivating factor and suggest that ghrelin may have therapeutic potential for the treatment of ALS and other neurodegenerative disorders where inflammatory responses play a critical role.

Ghrelin Protects Spinal Cord Motoneurons Against Chronic Glutamate Excitotoxicity by Inhibiting Microglial Activation

Lee, Sung-Youb,Kim, Yu-Mi,Li, Endan,Park, Seung-Joon The Korean Society of Pharmacology 2012 The Korean Journal of Physiology & Pharmacology Vol.16 No.1

Glutamate excitotoxicity is emerging as a contributor to degeneration of spinal cord motoneurons in amyotrophic lateral sclerosis (ALS). Recently, we have reported that ghrelin protects motoneurons against chronic glutamate excitotoxicity through the activation of extracellular signal-regulated kinase 1/2 and phosphatidylinositol-3-kinase/Akt/glycogen synthase kinase-$3{\beta}$ pathways. Previous studies suggest that activated microglia actively participate in the pathogenesis of ALS motoneuron degeneration. However, it is still unknown whether ghrelin exerts its protective effect on motoneurons via inhibition of microglial activation. In this study, we investigate organotypic spinal cord cultures (OSCCs) exposed to threohydroxyaspartate (THA), as a model of excitotoxic motoneuron degeneration, to determine if ghrelin prevents microglial activation. Exposure of OSCCs to THA for 3 weeks produced typical motoneuron death, and treatment of ghrelin significantly attenuated THA-induced motoneuron loss, as previously reported. Ghrelin prevented THA-induced microglial activation in the spinal cord and the expression of pro-inflammatory cytokines tumor necrosis factor-${\alpha}$ and interleukin-$1{\beta}$. Our data indicate that ghrelin may act as a survival factor for motoneurons by functioning as a microglia-deactivating factor and suggest that ghrelin may have therapeutic potential for the treatment of ALS and other neurodegenerative disorders where inflammatory responses play a critical role.

Human-to-mouse prion-like propagation of mutant huntingtin protein

Jeon, Iksoo,Cicchetti, Francesca,Cisbani, Giulia,Lee, Suji,Li, Endan,Bae, Jiwoo,Lee, Nayeon,Li, Ling,Im, Wooseok,Kim, Manho,Kim, Hyun Sook,Oh, Seung-Hun,Kim, Tae-Aug,Ko, Jung Jae,Aubé,, Benoit,O Springer Berlin Heidelberg 2016 Acta neuropathologica Vol.132 No.4

<P>Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder of the central nervous system (CNS) that is defined by a CAG expansion in exon 1 of the huntingtin gene leading to the production of mutant huntingtin (mHtt). To date, the disease pathophysiology has been thought to be primarily driven by cell-autonomous mechanisms, but, here, we demonstrate that fibroblasts derived from HD patients carrying either 72, 143 and 180 CAG repeats as well as induced pluripotent stem cells (iPSCs) also characterized by 143 CAG repeats can transmit protein aggregates to genetically unrelated and healthy host tissue following implantation into the cerebral ventricles of neonatal mice in a non-cell-autonomous fashion. Transmitted mHtt aggregates gave rise to both motor and cognitive impairments, loss of striatal medium spiny neurons, increased inflammation and gliosis in associated brain regions, thereby recapitulating the behavioural and pathological phenotypes which characterizes HD. In addition, both in vitro work using co-cultures of mouse neural stem cells with 143 CAG fibroblasts and the SH-SY5Y human neuroblastoma cell line as well as in vivo experiments conducted in newborn wild-type mice suggest that exosomes can cargo mHtt between cells triggering the manifestation of HD-related behaviour and pathology. This is the first evidence of human-to-mouse prion-like propagation of mHtt in the mammalian brain; a finding which will help unravel the molecular bases of HD pathology as well as to lead to the development of a whole new range of therapies for neurodegenerative diseases of the CNS.</P><P><B>Electronic supplementary material</B></P><P>The online version of this article (doi:10.1007/s00401-016-1582-9) contains supplementary material, which is available to authorized users.</P>