Bergapten alleviates Parkinson's disease-like behaviors in mice by inhibiting astrocyte inflammatory activation and endoplasmic reticulum stress through the regulation of the LCN2/JAK2/STAT3 pathway.

Parkinson disease (PD) is marked by a significant reduction in dopaminergic neurons in the substantia nigra pars compacta region of the brain. This neuronal loss is accompanied by aggregation of the α-synuclein protein, persistent endoplasmic reticulum (ER) stress, and disruption in the autophagy process. 18β-Glycyrrhetinic acid (18βGA), an oleanolic acid-type triterpenoid, has been shown to exhibit anti-inflammatory properties and neuroprotective effects. This study is the first to explore the potential neuroprotective effects of 18βGA in a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTP/p)-induced mouse model of PD, focusing on the role of ER stress and autophagy and examining the potential underlying mechanisms. MPTP/p-treated mice exhibited impaired motor function and elevated levels of α-synuclein and ER stress markers such as BiP, protein kinase RNA-like ER kinase (p-PERK), phosphorylated inositol-requiring enzyme 1 (p-IRE1), phosphorylated eukaryotic initiation factor α (p-eIF2α), and C/EBP homologous binding protein (CHOP). It also shows autophagy dysregulation, marked by increased phosphorylated c-Jun N-terminal kinase 1 (p-JNK-1), Beclin-1, and microtubule-associated protein 1 light chain 3 (LC3)-II, as well as autophagic vacuoles, and decreased B-cell lymphoma 2 (BCL-2) and p62. Treatment with 18βGA significantly improved motor performance, reduced α-synuclein accumulation, and restored tyrosine hydroxylase (TH) expression. It also attenuated ER stress markers, including BiP, p-PERK, p-IRE1, p-eIF2α, and CHOP. Moreover, 18βGA normalized autophagy-related alterations by decreasing p-JNK-1, Beclin-1, LC3-II, and autophagic vacuole formation, while increasing BCL-2 and p62 expression. These findings suggest that 18βGA confers neuroprotection by suppressing ER stress (via PERK and IRE1α pathways) and modulating autophagy through the BCL-2/Beclin-1 axis. Thus, 18βGA holds promise as a therapeutic candidate for Parkinson disease.

From adaption to death: endoplasmic reticulum stress as a novel target of selective neurodegeneration?

The pathogenesis of Parkinson's disease (PD) involves cellular processes such as endoplasmic reticulum (ER) stress, unfolded protein response, autophagy imbalance, and apoptosis, and identifying drugs that can regulate these molecular mechanisms may be a potential therapeutic strategy for PD. This study aimed to investigate the potential neuroprotective effects of the marine crinoid-derived natural compound (+)-rhodoptilometrin (RDM). We utilized an in vitro PD experimental model and conducted a biochemical analysis to investigate its potential neuroprotective effects against 6-hydroxydopamine (6-OHDA)-induced toxicity. We also examined its underlying molecular mechanisms, confirmed using the autophagy inhibitor 3-methyladenine. We utilized an in vivo PD model to evaluate motor function and verified the therapeutic effectiveness of the RDM. RDM effectively inhibited apoptosis, reduced ER stress, and enhanced the viability and autophagy of 6-OHDA-induced SH-SY5Y cells. This was evidenced by reductions in GRP78, p-eIF2α/eIF2α, XBP-1s, and C/EBP homologous protein levels alongside enhancements in LC3-related autophagy pathways. In vivo experiments using zebrafish also showed that RDM significantly attenuated the decrease in locomotor activity caused by 6-OHDA, concurrently alleviating GRP78-related ER stress and promoting antiapoptotic BCL2 expression. These findings indicate that RDM exerted neuroprotective effects by attenuating apoptosis, alleviating ER stress, and promoting autophagy pathways. RDM may be a promising antineurodegenerative drug.

Targeting the bile acid receptor TGR5 with Gentiopicroside to activate Nrf2 antioxidant signaling and mitigate Parkinson’s disease in an MPTP mouse model

PHB blocks endoplasmic reticulum stress and apoptosis induced by MPTP/MPP+ in PD models

The dysfunction of proteasomes and mitochondria has been implicated in the pathogenesis of Parkinson disease. However, the mechanism by which this dysfunction causes neuronal cell death is unknown. We studied the role of cyclin-dependent kinase 5 (Cdk5)-p35 in the neuronal cell death induced by 1-methyl-4-phenylpyrinidinium ion (MPP+), which has been used as an in vitro model of Parkinson disease. When cultured neurons were treated with 100 microM MPP+, p35 was degraded by proteasomes at 3 h, much earlier than the neurons underwent cell death at 12-24 h. The degradation of p35 was accompanied by the down-regulation of Cdk5 activity. We looked for the primary target of MPP+ that triggered the proteasome-mediated degradation of p35. MPP+ treatment for 3 h induced the fragmentation of the mitochondria, reduced complex I activity of the respiratory chain without affecting ATP levels, and impaired the mitochondrial import system. The dysfunction of the mitochondrial import system is suggested to up-regulate proteasome activity, leading to the ubiquitin-independent degradation of p35. The overexpression of p35 attenuated MPP+-induced neuronal cell death. In contrast, depletion of p35 with short hairpin RNA not only induced cell death but also sensitized to MPP+ treatment. These results indicate that a brief MPP+ treatment triggers the delayed neuronal cell death by the down-regulation of Cdk5 activity via mitochondrial dysfunction-induced up-regulation of proteasome activity. We propose a role for Cdk5-p35 as a survival factor in countering MPP+-induced neuronal cell death.

Modulation of endoplasmic reticulum stress in Parkinson's disease

Ginsenoside Re exerts neuroprotective in MPTP mice: potential links to gut microbiota and serum metabolism.

A specific polymorphism in the hemochromatosis (HFE) gene, H63D, is over-represented in neurodegenerative disorders such as amyotrophic lateral sclerosis and Alzheimer disease. Mutations of HFE are best known as being associated with cellular iron overload, but the mechanism by which HFE H63D might increase the risk of neuron degeneration is unclear. Here, using an inducible expression cell model developed from a human neuronal cell line SH-SY5Y, we reported that the presence of the HFE H63D protein activated the unfolded protein response (UPR). This response was followed by a persistent endoplasmic reticulum (ER) stress, as the signals of UPR sensors attenuated and followed by up-regulation of caspase-3 cleavage and activity. Our in vitro findings were recapitulated in a transgenic mouse model carrying Hfe H67D, the mouse equivalent of the human H63D mutation. In this model, UPR activation was detected in the lumbar spinal cord at 6 months then declined at 12 months in association with increased caspase-3 cleavage. Moreover, upon the prolonged ER stress, the number of cells expressing HFE H63D in early apoptosis was increased moderately. Cell proliferation was decreased without increased cell death. Additionally, despite increased iron level in cells carrying HFE H63D, it appeared that ER stress was not responsive to the change of cellular iron status. Overall, our studies indicate that the HFE H63D mutant protein is associated with prolonged ER stress and chronically increased neuronal vulnerability.

Palmitic acid (PA) upregulates oxidized LDL receptor-1 (LOX-1), a scavenger receptor responsible for uptake of oxidized LDL (oxLDL), and enhances oxLDL uptake in macrophages. However, the precise underlying mechanism remains to be elucidated. PA is known to induce endoplasmic reticulum (ER) stress in various cell types. Therefore, we investigated whether ER stress is involved in PA-induced LOX-1 upregulation. PA induced ER stress, as determined by phosphorylation of PERK, eIF2α, and JNK, as well as induction of CHOP in macrophage-like THP-1 cells. Inhibitors [4-phenylbutyric acid (PBA), sodium tauroursodeoxycholate (TUDCA), and salubrinal] and small interfering RNA (siRNA) for the ER stress response decreased PA-induced LOX-1 upregulation. Thapsigargin, an ER stress inducer, upregulated LOX-1, which was decreased by PBA and TUDCA. We next examined whether unsaturated FAs could counteract the effect of PA. Both oleic acid (OA) and linoleic acid (LA) suppressed PA-induced LOX-1. Activation of the ER stress response observed in the PA-treated cells was markedly attenuated when the cells were cotreated with OA or LA. In addition, OA and LA suppressed thapsigargin-induced LOX-1 upregulation with reduced activation of ER stress markers. Our results indicate that activation of ER stress is involved in PA-induced LOX-1 upregulation in macrophages, and that OA and LA inhibit LOX-1 induction through suppression of ER stress.

Aging is a major risk factor for the development of osteoarthritis (OA). One hallmark of aging is loss of proteostasis resulting in increased cellular stress and cell death. However, its effect on the development of OA is not clear. Here, using knee articular cartilage tissue from young and old cynomolgus monkeys (Macaca fascicularis), we demonstrate that with aging there is loss of molecular chaperone expression resulting in endoplasmic reticulum (ER) stress and cell death. Chondrocytes from aged articular cartilage showed decreased expression of molecular chaperones, including protein disulfide isomerase, calnexin, and Ero1-like protein alpha, and increased immunohistochemical staining for ER stress markers (phosphorylated IRE1 alpha, spliced X-box binding protein-1, activating transcription factor 4 and C/EBP homologous protein), and apoptotic markers [cleaved caspase 3 and cleaved poly(ADP-ribose) polymerase], suggesting that decreased expression of molecular chaperone during aging induces ER stress and chondrocyte apoptosis in monkey articular cartilage. Apoptosis induced by aging-associated ER stress was further confirmed by TUNEL staining. Aged monkey cartilage also showed increased expression of nuclear protein 1 (Nupr1) and tribbles related protein-3 (TRB3), known regulators of apoptosis and cell survival pathways. Treatment of cultured monkey chondrocytes with a small molecule chemical chaperone, 4-phenylbutyric acid (PBA, a general ER stress inhibitor) or PERK Inhibitor I (an ER stress inhibitor specifically targeting the PERK branch of the unfolded protein response pathway), decreased the expression of ER stress and apoptotic markers and reduced the expression of Nupr1 and TRB3. Consistent with the above finding, knockdown of calnexin expression induces ER stress and apoptotic markers in normal human chondrocytes in vitro. Taken together, our study clearly demonstrates that aging promotes loss of proteostasis and induces ER stress and chondrocyte apoptosis in articular cartilage. Thus, restoring proteostasis using chemical/molecular chaperone or ER stress inhibitor could be a therapeutic option to treat aged-linked OA.

Parkinson’s disease (PD) is the second most common neurodegenerative disease worldwide, and accumulating evidence indicates that mitochondrial dysfunction is associated with progressive deterioration in PD patients. Previous studies have shown that sinapic acid has a neuroprotective effect, but its mechanisms of action remain unclear. The neuroprotective effect of sinapic acid was assayed in a PD mouse model generated by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as well as in SH-SY5Y cells. Target protein expression was detected by western blotting. Sinapic acid treatment attenuated the behavioral defects and loss of dopaminergic neurons in the PD models. Sinapic acid also improved mitochondrial function in the PD models. MPTP treatment increased the abundance of mitochondrial fission proteins such as dynamin-related protein 1 (Drp1) and phospho-Drp1 Ser616. In addition, MPTP decreased the expression of the REV-ERB α protein. These changes were attenuated by sinapic acid treatment. We used the pharmacological REV-ERB α inhibitor SR8278 to confirmation of protective effect of sinapic acid. Treatment of SR8278 with sinapic acid reversed the protein expression of phospho-Drp1 Ser616 and REV-ERB α on MPTP-treated mice. Our findings demonstrated that sinapic acid protects against MPTP-induced PD and these effects might be related to the inhibiting abnormal mitochondrial fission through REV-ERB α.

Details Unfold: The Endoplasmic Reticulum Stress Response in Intestinal Inflammation and Cancer

Parkinson's disease (PD) is the second most common neurodegenerative disorder in worldwide and remains a therapeutic challenge due to the low efficacy of current treatments. Numerous studies have demonstrated the pivotal role of endoplasmic reticulum (ER) stress in PD pathogenesis. ER stress, followed by activation of the protein kinase RNA‑like endoplasmic reticulum kinase (PERK)‑dependent branch of the unfolded protein response signaling pathway, ultimately leads to neural cell death and dopaminergic neurodegeneration in PD. Therefore, the present study evaluated the effectiveness of the small‑molecule PERK inhibitor LDN‑87357 in an invitro PD model using the human neuroblastoma SH‑SY5Y cell line. To assess the mRNA expression levels of the pro‑apoptotic ER stress markers, the TaqMan Gene Expression Assay was performed. Cytotoxicity was assessed using a colorimetric 2,3‑bis‑(2‑methoxy‑4‑nitro‑5‑sulfophenyl)‑ 2H‑tetrazolium‑5‑carboxanilide assay and apoptosis was assessed using a caspase‑3 assay. Moreover, cell cycle progression was evaluated using flow cytometry. The results indicated that LDN‑87357 treatment induced a significant decrease in ER stress markers gene expression in SH‑SY5Y cells exposed to ER stress. Furthermore, LDN‑87357 significantly increased viability, diminished apoptosis and restored the normal cell cycle distribution of SH‑SY5Y cells after ER stress induction. Therefore, the evaluation of small‑molecule PERK inhibitors, such as LDN‑87357, may lead to the development of novel therapeutic strategies against PD.

Parkinson's disease (PD) is a common neurodegenerative disorder with motor symptoms, which is caused by the progressive death of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). Accumulating evidence shows that endoplasmic reticulum (ER) stress occurring in the SNpc DA neurons is an early event in the development of PD. ER stress triggers the activation of unfolded protein response (UPR) to reduce stress and restore ER function. However, excessive and continuous ER stress and UPR exacerbate the risk of DA neuron death through crosstalk with other PD events. Thus, ER stress is considered a promising therapeutic target for the treatment of PD. Various strategies targeting ER stress through the modulation of UPR signaling, the increase of ER's protein folding ability, and the enhancement of protein degradation are developed to alleviate neuronal death in PD models. In this review, we summarize the pathological role of ER stress in PD and update the strategies targeting ER stress to improve ER protein homeostasis and PD-related events.