作者: Karch, Celeste M ; Petersen, Cathrine ; Temple, Sally ; Khan, Shireen ; Wang, Chao ; Grinberg, Lea T ; Butler, David ; Kayed, Rakez ; Gestwicki, Jason E ; Theofilas, Panos ; Arkin, Michelle R ; Yang, Teddy ; Miller, Bruce L ; Chin, Brian ; Gan, Li ; Ng, Raymond ; Morales, Dulce O ; Ambrose, Andrew

BACKGROUNDTau post-translational modifications (PTMs) result in the gradual build-up of abnormal tau and neuronal degeneration in tauopathies, encompassing variants of frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD). Tau proteolytically cleaved by active caspases, including caspase-6, may be neurotoxic and prone to self-aggregation. Also, our recent findings show that caspase-6 truncated tau represents a frequent and understudied aspect of tau pathology in AD in addition to phospho-tau pathology. In AD and Pick's disease, a large percentage of caspase-6 associated cleaved-tau positive neurons lack phospho-tau, suggesting that many vulnerable neurons to tau pathology go undetected when using conventional phospho-tau antibodies and possibly will not respond to phospho-tau based therapies. Therefore, therapeutic strategies against caspase cleaved-tau pathology could be necessary to modulate the extent of tau abnormalities in AD and other tauopathies.METHODSTo understand the timing and progression of caspase activation, tau cleavage, and neuronal death, we created two mAbs targeting caspase-6 tau cleavage sites and probed postmortem brain tissue from an individual with FTLD due to the V337M MAPT mutation. We then assessed tau cleavage and apoptotic stress response in cortical neurons derived from induced pluripotent stem cells (iPSCs) carrying the FTD-related V337M MAPT mutation. Finally, we evaluated the neuroprotective effects of caspase inhibitors in these iPSC-derived neurons.RESULTSFTLD V337M MAPT postmortem brain showed positivity for both cleaved tau mAbs and active caspase-6. Relative to isogenic wild-type MAPT controls, V337M MAPT neurons cultured for 3 months post-differentiation showed a time-dependent increase in pathogenic tau in the form of caspase-cleaved tau, phospho-tau, and higher levels of tau oligomers. Accumulation of toxic tau species in V337M MAPT neurons was correlated with increased vulnerability to pro-apoptotic stress. Notably, this mutation-associated cell death was pharmacologically rescued by the inhibition of effector caspases.CONCLUSIONSOur results suggest an upstream, time-dependent accumulation of caspase-6 cleaved tau in V337M MAPT neurons promoting neurotoxicity. These processes can be reversed by caspase inhibition. These results underscore the potential of developing caspase-6 inhibitors as therapeutic agents for FTLD and other tauopathies. Additionally, they highlight the promise of using caspase-cleaved tau as biomarkers for these conditions.

2018-06-01·Neuropsychopharmacology1区 · 医学

Disruption of lipid-raft localized Gαs/tubulin complexes by antidepressants: a unique feature of HDAC6 inhibitors, SSRI and tricyclic compounds

1区 · 医学

Article

作者: Schappi, Jeffrey M ; Wray, Nathan ; Singh, Harinder ; Rasenick, Mark M

Current antidepressant therapies meet with variable therapeutic success and there is increasing interest in therapeutic approaches not based on monoamine signaling. Histone deacetylase 6 (HDAC6), which also deacetylates α-tubulin shows altered expression in mood disorders and HDAC6 knockout mice mimic traditional antidepressant treatments. Nonetheless, a mechanistic understanding for HDAC6 inhibitors in the treatment of depression remains elusive. Previously, we have shown that sustained treatment of rats or glioma cells with several antidepressants translocates Gα_s from lipid rafts toward increased association with adenylyl cyclase (AC). Concomitant with this is a sustained increase in cAMP production. While Gα_s modifies microtubule dynamics, tubulin also acts as an anchor for Gα_s in lipid-rafts. Since HDAC-6 inhibitors potentiate α-tubulin acetylation, we hypothesize that acetylation of α-tubulin disrupts tubulin-Gα_s raft-anchoring, rendering Gα_s free to activate AC. To test this, C6 Glioma (C6) cells were treated with the HDAC-6 inhibitor, tubastatin-A. Chronic treatment with tubastatin-A not only increased α-tubulin acetylation but also translocated Gα_s from lipid-rafts, without changing total Gα_s. Reciprocally, depletion of α-tubulin acetyl-transferase-1 ablated this phenomenon. While escitalopram and imipramine also disrupt Gα_s/tubulin complexes and translocate Gα_s from rafts, they evoke no change in tubulin acetylation. Finally, two indicators of downstream cAMP signaling, cAMP response element binding protein phosphorylation (pCREB) and expression of brain-derived-neurotrophic-factor (BDNF) were both elevated by tubastatin-A. These findings suggest HDAC6 inhibitors show a cellular profile resembling traditional antidepressants, but have a distinct mode of action. They also reinforce the validity of antidepressant-induced Gα_s translocation from lipid-rafts as a biosignature for antidepressant response that may be useful in the development of new antidepressant compounds.

2015-05-01·Human Molecular Genetics2区 · 生物学

A Huntingtin-based peptide inhibitor of caspase-6 provides protection from mutant Huntingtin-induced motor and behavioral deficits

2区 · 生物学

Article

作者: Shruster, Adi ; Offen, Daniel ; Ehrnhoefer, Dagmar E ; Hayden, Michael R ; Franciosi, Sonia ; Qiu, Xiaofan ; Aharony, Israel

Over the past decade, increasing evidence has implied a significant connection between caspase-6 activity and the pathogenesis of Huntington's disease (HD). Consequently, inhibiting caspase-6 activity was suggested as a promising therapeutic strategy to reduce mutant Huntingtin toxicity, and to provide protection from mutant Huntingtin-induced motor and behavioral deficits. Here, we describe a novel caspase-6 inhibitor peptide based on the huntingtin caspase-6 cleavage site, fused with a cell-penetrating sequence. The peptide reduces mutant Huntingtin proteolysis by caspase-6, and protects cells from mutant Huntingtin toxicity. Continuous subcutaneous administration of the peptide protected pre-symptomatic BACHD mice from motor deficits and behavioral abnormalities. Moreover, administration of the peptide in an advanced disease state resulted in the partial recovery of motor performance, and an alleviation of depression-related behavior and cognitive deficits. Our findings reveal the potential of substrate-based caspase inhibition as a therapeutic strategy, and present a promising agent for the treatment of HD.

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适应症	最高研发状态	国家/地区	公司	日期
肝纤维化	临床前	美国	Elgia Therapeutics, Inc.初创企业	2024-07-12
肾脏疾病	临床前	美国	Elgia Therapeutics, Inc.初创企业	2024-07-12
神经炎症	临床前	美国	Elgia Therapeutics, Inc.初创企业	2024-07-12