Involvement of molecular chaperone in protein-misfolding brain diseases

Wankhede, Nitu L.; Kale, Mayur B.; Upaganlawar, Aman; Taksande, Brijesh G.; Umekar, Milind J.; Behl, Tapan; Abdellatif, Ahmed A. H.; Bhaskaran, Prasanna Mohana; Dachani, Sudharshan Reddy; Sehgal, Aayush; Singh, Sukhbir; Sharma, Neelam; Makeen, Hafiz A.; Albratty, Mohammed; Dailah, Hamed Ghaleb; Bhatia, Saurabh; Al‐Harrasi, Ahmed; Bungău, Simona

doi:10.1016/j.biopha.2022.112647

Cited by 31 publications

(10 citation statements)

References 240 publications

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“…Molecular chaperones prevent protein misfolding and aggregation-induced neurotoxicity. A growing body of evidence suggests that they play a significant role in neuron degeneration and may participate in Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease [ 39 ]. Okuyama et al [ 40 ] described that the accumulation of misfolded proteins in the endoplasmic reticulum (ER) induced the unfolded protein response (UPS) contributing to diverse pathological conditions, such as opioid tolerance development.…”

Section: Resultsmentioning

confidence: 99%

The Dose-Dependent Effects of Multifunctional Enkephalin Analogs on the Protein Composition of Rat Spleen Lymphocytes, Cortex, and Hippocampus; Comparison with Changes Induced by Morphine

et al. 2022

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This work aimed to test the effect of 7-day exposure of rats to multifunctional enkephalin analogs LYS739 and LYS744 at doses of 3 mg/kg and 10 mg/kg on the protein composition of rat spleen lymphocytes, brain cortex, and hippocampus. Alterations of proteome induced by LYS739 and LYS744 were compared with those elicited by morphine. The changes in rat proteome profiles were analyzed by label-free quantification (MaxLFQ). Proteomic analysis indicated that the treatment with 3 mg/kg of LYS744 caused significant alterations in protein expression levels in spleen lymphocytes (45), rat brain cortex (31), and hippocampus (42). The identified proteins were primarily involved in RNA processing and the regulation of cytoskeletal dynamics. In spleen lymphocytes, the administration of the higher 10 mg/kg dose of both enkephalin analogs caused major, extensive modifications in protein expression levels: LYS739 (119) and LYS744 (182). Among these changes, the number of proteins associated with immune responses and apoptotic processes was increased. LYS739 treatment resulted in the highest number of alterations in the rat brain cortex (152) and hippocampus (45). The altered proteins were functionally related to the regulation of transcription and cytoskeletal reorganization, which plays an essential role in neuronal plasticity. Administration with LYS744 did not increase the number of altered proteins in the brain cortex (26) and hippocampus (26). Our findings demonstrate that the effect of κ-OR full antagonism of LYS744 is opposite in the central nervous system and the peripheral region (spleen lymphocytes).

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Section: Resultsmentioning

confidence: 99%

The Dose-Dependent Effects of Multifunctional Enkephalin Analogs on the Protein Composition of Rat Spleen Lymphocytes, Cortex, and Hippocampus; Comparison with Changes Induced by Morphine

et al. 2022

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“…This disease has a high social and economic impact, and there are no definitive treatments to date. Although the accumulation of Aβ-plaques and tau protein fibrils in the brain is acknowledged as being the primary pathological condition of AD [ 1 ], the relationship to clinical manifestations as well as the underlying causes of its pathophysiological mechanism have not been elucidated so far [ 2 ]. In the last years, many radiolabeled ligands have shown a tropism for Aβ-aggregates and tau proteins and have been employed for preclinical studies or clinical trials [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Radiolabeled Chalcone Derivatives as Potential Radiotracers for β-Amyloid Plaques Imaging

et al. 2023

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Natural products often provide a pool of pharmacologically relevant precursors for the development of various drug-related molecules. In this review, the research performed on some radiolabeled chalcone derivatives characterized by the presence of the α-β unsaturated carbonyl functional group as potential radiotracers for the imaging of β-amyloids plaques will be summarized. Chalcones’ structural modifications and chemical approaches which allow their radiolabeling with the most common SPECT (Single Photon Emission Computed Tomography) and PET (Positron Emission Tomography) radionuclides will be described, as well as the state of the art regarding their in vitro binding affinity and in vivo biodistribution and pharmacokinetics in preclinical studies. Moreover, an explanation of the rationale behind their potential utilization as probes for Alzheimer’s disease in nuclear medicine applications will be provided.

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“…molecular chaperones are known to play a critical role in homeostasis of nAChRs (Colombo et al, 2013; Crespi et al, 2018). Several of them including heat shock proteins interact with disease‐related proteins such as amyloid‐β in Alzheimer's disease (AD), α‐synuclein in Parkinson's disease (PD) and superoxide dismutase 1 in amyotrophic lateral sclerosis (ALS) (Wankhede et al, 2022). Mutations in PD gene DNAJC6 (DnaJ heat shock protein family (Hsp40) member C6) and co‐chaperone VCP (valosin‐containing protein) are known to cause juvenile Parkinsonism (Edvardson et al, 2012) and ALS (Johnson et al, 2010) respectively.…”

Section: Introductionmentioning

confidence: 99%

Deletion induced splicing in RIC3 drives nicotinic acetylcholine receptor regulation with implications for endoplasmic reticulum stress in human astrocytes

Yadav

Thelma

2023

Glia

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Nicotinic acetylcholine receptor (nAChR) dysregulation in astrocytes is reported in neurodegenerative disorders. Modulation of nAChRs through agonists confers protection to astrocytes from stress but regulation of chaperones involved in proteostasis with pathological implications is unclear. Resistance to inhibitors of cholinesterase 3 (RIC3), a potential chaperone of nAChRs is poorly studied in humans. We characterized RIC3 in astrocytes derived from an isogenic wild-type and Cas9 edited "del" human iPSC line harboring a 25 bp homozygous deletion in exon2. Altered RIC3 transcript ratio due to deletion induced splicing and an unexpected gain of α7nAChR expression were observed in "del" astrocytes. Transcriptome analysis showed higher expression of neurotransmitter/G-protein coupled receptors mediated by cAMP and calcium/calmodulin-dependent kinase signaling with increased cytokines/glutamate secretion. Functional implications examined using tunicamycin induced ER stress in wild-type astrocyte stress model showed cell cycle arrest, RIC3 upregulation, reduction in α7nAChR membrane levels but increased α4nAChR membrane expression.Conversely, tunicamycin-treated "del" astrocytes showed a comparatively higher α4nAChR membrane expression and upsurged cAMP signaling. Furthermore, reduced expression of stress markers CHOP, phospho-PERK and lowered XBP1 splicing in western blot and qPCR, validated by proteome-based pathway analysis indicated lowered disease severity. Findings indicate (i) a complex RNA regulatory mechanism via exonic deletion induced splicing; (ii) RIC-3 as a disordered protein having contrasting effects on co-expressed nAChR subtypes under basal/stress conditions; and (iii) RIC3 as a potential drug target against ER stress in astrocytes for neurodegenerative/nicotine-related brain disorders. Cellular rescue mechanism through deletion induced exon skipping may encourage ASO-based therapies for tauopathies.

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Involvement of molecular chaperone in protein-misfolding brain diseases

Cited by 31 publications

References 240 publications

The Dose-Dependent Effects of Multifunctional Enkephalin Analogs on the Protein Composition of Rat Spleen Lymphocytes, Cortex, and Hippocampus; Comparison with Changes Induced by Morphine

The Dose-Dependent Effects of Multifunctional Enkephalin Analogs on the Protein Composition of Rat Spleen Lymphocytes, Cortex, and Hippocampus; Comparison with Changes Induced by Morphine

Radiolabeled Chalcone Derivatives as Potential Radiotracers for β-Amyloid Plaques Imaging

Deletion induced splicing in RIC3 drives nicotinic acetylcholine receptor regulation with implications for endoplasmic reticulum stress in human astrocytes

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