Accumulation of misfolded and aggregation-prone proteins is the common hallmark of many neurodegenerative disorders, and lowering the levels of these proteins may provide promising strategies for the potential treatment of some of these diseases.Among them, Huntington's disease (HD) is a monogenic disease caused by mutation of the HTT (huntingtin) gene, which encodes the mutant HTT protein (mHTT) with an expanded polyglutamine tract (polyQ).The monogenetic nature of HD provides high confidence for the causal relationship between mHTT and disease pathol., making HD suitable for testing the potential beneficial effects of reducing disease-causing proteins.In this study, we elucidated the potential role of HIPK3 in HD pathogenesis and the possible therapeutic effects of the small-mol. HIPK3 inhibitor AST487 in HD models, including HD mouse primary neurons, human induced pluripotent stem cell (iPSC)-derived neurons, and HD fly models.We first investigated the potential pathol. role of HIPK3 in HD.The mHTT-induced cytotoxicity under stressed culture conditions occurred in neurons from a knock-in mouse model (HD Q7/Q140, Q indicates polyglutamine) expressing endogenous mHTT protein from its original locus.Knocking down HIPK3 rescued the apoptotic phenotype.To further confirm the role of Hipk3 in vivo, we tested two HD Drosophila models.A loss-of- function (LOF) mutation of the Drosophila homolog of Hipk3 (Hipk-LOF) significantly decreased the mHTT level in the HD transgenic model expressing the N-terminal fragment of human mHTT with 128Q.Here, we further showed that HIPK3 RNAi (RNA interference) or AST487 treatment enhanced the autophagosome marker protein LC3B-II levels in mouse primary neurons and human iPSC-derived neurons, indicating that the autophagy level was up-regulated. HIPK3 RNAi decreased the caspase signal, and significantly decreased the cleaved caspase 3 in mouse primary neurons and human iPSC-derived neurons, suggesting that HIPK3 is involved in the pathogenesis in HD neurons.The HTT protein is very large (348 kDa), its entire crystal structure and function are still unknown, so it is very difficult to develop therapeutic drugs that target it.The current study provides both genetic and chem. biol. evidence demonstrating that HIPK3 is a potential thera- peutic target of HD: knocking down HIPK3 or treatment with the HIPK3 inhibitor AST487.Thus, targeting the kinase HIPK3 to lower the mHTT level would be a potential direction for developing HD drugs.Collectively, targeting HIPK3 using small-mol. inhibitors could be beneficial to HD patients, while further optimization of the compounds and further in vivo studies in the HD mouse models are needed.

01 Nov 2020·American Journal of Physiology-Renal PhysiologyQ3 · MEDICINE

Involvement of the CDKL5-SOX9 signaling axis in rhabdomyolysis-associated acute kidney injury

Q3 · MEDICINE

Article

Author: Bai, Yuntao ; Cianciolo, Rachel E. ; Jayne, Laura A. ; Bajwa, Amandeep ; Pabla, Navjot Singh ; Kim, Ji Young

Acute kidney injury (AKI) is a common clinical syndrome associated with adverse short- and long-term sequelae. Renal tubular epithelial cell (RTEC) dysfunction and cell death are among the key pathological features of AKI. Diverse systemic and localized stress conditions such as sepsis, rhabdomyolysis, cardiac surgery, and nephrotoxic drugs can trigger RTEC dysfunction. Through an unbiased RNA inhibition screen, we recently identified cyclin-dependent kinase-like 5 (Cdkl5), also known as serine/threonine kinase-9, as a critical regulator of RTEC dysfunction associated with nephrotoxic and ischemia-associated AKI. In the present study, we examined the role of Cdkl5 in rhabdomyolysis-associated AKI. Using activation-specific antibodies and kinase assays, we found that Cdkl5 is activated in RTECs early during the development of rhabdomyolysis-associated AKI. Furthermore, we found that RTEC-specific Cdkl5 gene ablation mitigates rhabdomyolysis-associated renal impairment. In addition, the small-molecule kinase inhibitor AST-487 alleviated rhabdomyolysis-associated AKI in a Cdkl5-dependent manner. Mechanistically, we demonstrated that Cdkl5 phosphorylates the transcriptional regulator sex-determining region Y box 9 (Sox9) and suppresses its protective function under stress conditions. On the basis of these results, we propose that, by suppressing the protective Sox9-directed transcriptional program, Cdkl5 contributes to rhabdomyolysis-associated renal impairment. All together, the present study identified Cdkl5 as a critical stress-induced kinase that drives RTEC dysfunction and kidney injury linked with distinct etiologies.

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Indication	Highest Phase	Country/Location	Organization	Date
Thyroid Cancer, Medullary	Preclinical	Switzerland	Novartis AG	17 Jul 2007

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