CHIP protects against MPP+/MPTP-induced damage by regulating Drp1 in two models of Parkinson’s disease

Hu, Z. W.; Mao, Chengyuan; Wang, Hui; Zhang, Zhongxian; Zhang, Shuo; Luo, Hui; Tang, Mibo; Yang, Jing; Yuan, Yanpeng; Wang, Yanlin; Liu, Yutao; Fan, Liyuan; Zhang, Qimeng; Yao, Dabao; Liu, Fen; Schisler, Jonathan C.; Shi, Changhe; Xu, Yuming

doi:10.18632/aging.202389

Cited by 14 publications

(8 citation statements)

References 40 publications

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“…The adeno-associated viral vector is an effective CNS gene delivery method that can cross the blood-brain barrier [ 49 ]. Our previous study showed that adeno-associated viruses carrying the CHIP gene can upregulate CHIP expression in the mouse brain and exert protective effects in a Parkinson’s disease mouse model [ 50 ], which showed that the adeno-associated viral platform may be an efficient way to upregulate CHIP expression in the CNS. Overall, developing a safe and effective method that can induce CHIP overexpression in the CNS for CIR injury treatment may be the focus of future research.…”

Section: Discussionmentioning

confidence: 99%

“…Adult male mice (aged 10–12 weeks, weighing 25–30 g; Henan Experimental Animal Center, Henan, China), including WT C57BL/6 mice and CHIP KI mice with a C57BL/6 background, were used in this study. CHIP KI mice were constructed as described in our previous study [ 50 ]. Briefly, CRISPR/Cas9 technology was used to construct CHIP-with-floxed-STOP-codon mice, which were crossed with Nestin-cre mice to obtain NES-CHIP mice (we named CHIP KI mice here).…”

Section: Methodsmentioning

confidence: 99%

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CHIP ameliorates cerebral ischemia-reperfusion injury by attenuating necroptosis and inflammation

Yao

Zhang

et al. 2021

Aging

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Blood reperfusion of ischemic cerebral tissue may cause cerebral ischemia-reperfusion (CIR) injury. Necroptosis and inflammation have been demonstrated to be involved in the disease-related process of CIR injury. The E3 ubiquitin ligase carboxyl terminus of Hsp70-interacting protein (CHIP) can modulate multiple cellular signaling processes, including necroptosis and inflammation. Numerous studies have demonstrated the neuroprotective effects of CHIP on multiple central nervous system (CNS) diseases. However, the effects of CHIP on CIR injury have not been fully explored. We hypothesize that CHIP can exert neuroprotective effects by attenuating necroptosis and inflammation during CIR injury. In the present study, adult wild-type (WT) C57BL/6 mice and CHIP knock-in (KI) mice with a C57BL/6 background and CHIP overexpression in neural tissue underwent middle cerebral artery occlusion (MCAO) surgery to simulate CIR onset. Our data indicated that CHIP expression in the peri-infarct tissue was markedly increased after MCAO surgery. Compared with WT mice, CHIP KI mice significantly improved neurological deficit scores, decreased cerebral infarct volume, and attenuated brain edema and neuronal damage. Meanwhile, CHIP overexpression attenuated necroptosis and inflammation induced by MCAO surgery. These findings indicated that overexpression of CHIP might exert neuroprotective effects by attenuating necroptosis and inflammation during CIR injury, and increasing CHIP levels may be a potential strategy in cerebrovascular disease therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

CHIP ameliorates cerebral ischemia-reperfusion injury by attenuating necroptosis and inflammation

Yao

Zhang

et al. 2021

Aging

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“…The packaged AAVs were at the following titers: AAV-TFEB-overexpression (TFEB, 1.5 × 10 12 ), AAV-NULL (NULL, 1.6 × 10 12 ), TFEB shRNA (shTFEB, 1.6 × 10 12 ) and AAV-nontarget shRNA (shNT, 1.7 × 10 12 ) genome copies per milliliter. The AAV-BBB2.0 vector was delivered to the brain via tail vein injection (100 μL each), as this specific AAV type can cross the brain blood barrier [ 34 , 35 ].…”

Section: Methodsmentioning

confidence: 99%

mTOR-dependent TFEB activation and TFEB overexpression enhance autophagy-lysosome pathway and ameliorate Alzheimer's disease-like pathology in diabetic encephalopathy

et al. 2023

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Background Diabetic encephalopathy (DE) is a complication of type 2 diabetes mellitus (T2DM) that features Alzheimer's disease (AD)-like pathology, which can be degraded by the autophagy-lysosome pathway (ALP). Since transcription factor EB (TFEB) is a master regulator of ALP, TFEB-mediated ALP activation might have a therapeutic effect on DE, but this has yet to be investigated. Methods We established T2DM mouse models and cultured HT22 cells under high-glucose (HG) conditions to confirm the role of ALP in DE. To further investigate this, both mice and HT22 cells were treated with 3-methyladenine (3-MA). We also analyzed the content of TFEB in the nucleus and cytoplasm to evaluate its role in ALP. To confirm the effect of TFEB activation at the post-translational level in DE, we used rapamycin to inhibit the mechanistic target of rapamycin (mTOR). We transduced both mice and cells with TFEB vector to evaluate the therapeutic effect of TFEB overexpression on DE. Conversely, we conducted TFEB knockdown to verify its role in DE in another direction. Results We found that T2DM mice experienced compromised cognitive function, while HG-cultured HT22 cells exhibited increased cell apoptosis. Additionally, both T2DM mice and HG-cultured HT22 cells showed impaired ALP and heavier AD-like pathology. This pathology worsened after treatment with 3-MA. We also observed decreased TFEB nuclear translocation in both T2DM mice and HG-cultured HT22 cells. However, inhibiting mTOR with rapamycin or overexpressing TFEB increased TFEB nuclear translocation, enhancing the clearance of ALP-targeted AD-like pathology. This contributed to protection against neuronal apoptosis and alleviation of cognitive impairment. Conversely, TFEB knockdown lessened ALP-targeted AD-like pathology clearance and had a negative impact on DE. Conclusion Our findings suggest that impaired ALP is responsible for the aggravation of AD-like pathology in T2DM. We propose that mTOR-dependent TFEB activation and TFEB overexpression are promising therapeutic strategies for DE, as they enhance the clearance of ALP-targeted AD-like pathology and alleviate neuronal apoptosis. Our study provides insight into the underlying mechanisms of DE and offers potential avenues for the development of new treatments for this debilitating complication of T2DM. Graphic Abstract

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“…59 Moreover, it was found that overexpression of CHIP ameliorates MPTP toxicity in the SH-SY5Y cell line. 60 2.1.7. Silent Mating Type Information Regulation 2 Homolog (Sirtuin).…”

Section: C-terminus Of Hsc70-interacting Protein (Chip)mentioning

confidence: 99%

Uncovering Novel Therapeutic Targets for Parkinson’s Disease

Soni

Delvadia

Joharapurkar

et al. 2023

ACS Chem. Neurosci.

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Parkinson's disease (PD) is the second most prevailing progressive disorder leading to neurodegeneration, typically in people above 65 years of age. Motor clinical manifestations of PD appear in a much later stage and include rigidity, tremors, akinesia, and gait dysfunction. There are also nonmotor symptoms like GI and olfactory dysfunction. However, they cannot be considered for diagnosis of the disease, as they are unspecific. PD pathogenesis is mainly characterized by deposits of inclusion bodies on dopaminergic (DA) neurons in substantia nigra pars compacta region (SNpc) of the brain. The major component of these inclusion bodies, are αsynuclein aggregates. α-Synuclein undergoes misfolding and oligomerization to form aggregates and fibrils. These aggregates gradually propagate PD pathology. Other prominent features of this pathological development include mitochondrial dysfunction, neuroinflammation, oxidative stress, and impaired autophagy. These all contribute to neuronal degeneration. Besides this, there are many underlying factors which influence these processes. These factors comprise molecular proteins and signaling cascades. In this review, we have listed out underexplored molecular targets that may aid in development of neoteric and advanced therapeutics.

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CHIP protects against MPP+/MPTP-induced damage by regulating Drp1 in two models of Parkinson’s disease

Cited by 14 publications

References 40 publications

CHIP ameliorates cerebral ischemia-reperfusion injury by attenuating necroptosis and inflammation

CHIP ameliorates cerebral ischemia-reperfusion injury by attenuating necroptosis and inflammation

mTOR-dependent TFEB activation and TFEB overexpression enhance autophagy-lysosome pathway and ameliorate Alzheimer's disease-like pathology in diabetic encephalopathy

Uncovering Novel Therapeutic Targets for Parkinson’s Disease

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