Parkin, PINK1 and DJ1 as possible modulators of mTOR pathway in ganglioglioma

Drapalo, Katarzyna; Jóźwiak, Jarosław

doi:10.1080/00207454.2017.1366906

Cited by 10 publications

(8 citation statements)

References 49 publications

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“…Given the prominent role of chronic iron exposure in AD, and the increased autophagy latency in the development of severe neuron loss caused by iron accumulation, we then investigated the contribution of autophagy to brain damage. m-TOR is an evolutionarily conserved PI3-kinase family member that plays a key role in integrating different biochemical and growth factor signals, and regulates the occurrence of autophagy [39]. We found that HDI treatment did not significantly affect m-TOR expression in WT mice, but significantly increased its expression in AD model mice (Figure 7(A1,B1), p < 0.01), whereas HDI treatment significantly decreased p-m-TOR expression in both groups (Figure 7(A2,B2), p < 0.01).…”

Section: Resultsmentioning

confidence: 99%

“…We found that levels of p-m-TOR were dramatically decreased by HDI treatment, whereas the levels of calpain-1, Beclin-1, LC3A/B, and p62 were elevated. m-TOR is a variety of intracellular protein receptor that regulates the occurrence of autophagy [39]. The observed suppressed phosphorylation of m-TOR indicated that autophagy is induced by HDI treatment in the brain of both WT and APP/PS1 mice [72].…”

Section: Discussionmentioning

confidence: 99%

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Iron Exposure and the Cellular Mechanisms Linked to Neuron Degeneration in Adult Mice

Chai

Zhang

et al. 2019

Cells

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Although the causal relationship between Alzheimer’s disease (AD) and iron overload remains unclear, iron dyshomeostasis or improper transport mechanisms are speculated to lead to the accumulation of this neurotoxic metal in the hippocampal formation and other cerebral areas related to neurodegenerative diseases, resulting in the formation of reactive oxygen species (ROS) and, ultimately, cell death. In this study, exposure to high dietary iron (HDI) revealed no significant difference in the number of iron-positive cells and iron content in the cortex and hippocampal region between wild-type (WT) and APP/PS1 mice; however, compared with the control mice, the HDI-treated mice exhibited upregulated divalent metal transporter 1 (DMT1) and ferroportin (Fpn) expression, and downregulated transferrin receptor (TFR) expression. Importantly, we confirmed that there were significantly fewer NeuN-positive neurons in both APP/PS1 and WT mice given HDI, than in the respective controls. Moreover, this iron-induced neuron loss may involve increased ROS and oxidative mitochondria dysfunction, decreased DNA repair, and exacerbated apoptosis and autophagy. Although HDI administration might trigger protective antioxidant, anti-apoptosis, and autophagy signaling, especially in pathological conditions, these data clearly indicate that chronic iron exposure results in neuronal loss due to apoptosis, autophagy, and ferroptosis, hence increasing the risk for developing AD.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Iron Exposure and the Cellular Mechanisms Linked to Neuron Degeneration in Adult Mice

Chai

Zhang

et al. 2019

Cells

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“…The specific regulatory factors of mitochondrial autophagy have not been completely elucidated (5). However, increasing numbers of studies have linked mitochondrial autophagy function to Parkin (6)(7)(8). In patients with Parkin mutations, the activity of the mitochondrial complex has been demonstrated to be reduced in leucocytes; rat Parkin knockout models exhibit reduced mitochondrial proteins and certain mitochondrial deficits, and an increased vulnerability towards autophagy function was observed in a Parkin deletion model (9).…”

Section: Introductionmentioning

confidence: 99%

Parkin deficiency elevates hepatic ischemia/reperfusion injury accompanying decreased mitochondrial autophagy, increased apoptosis, impaired DNA damage repair and altered cell cycle distribution

et al. 2018

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Hepatic ischemia/reperfusion injury (HIRI) serves a causative role in postoperative hepatocyte death; however, the mechanisms underlying HIRI remain unclear. Mitochondrial autophagy, with apoptosis, cell cycle distribution and DNA damage repair, may be regarded as a regulatory factor post-HIRI. Parkin, a novel ubiquitin ligase, has been reported to increase mitochondrial autophagy and decrease apoptosis. However, the association between Parkin, mitochondrial autophagy and other regulatory factors in HIRI is unclear. In the present study, the effects of Parkin on HIRI were investigated, using hepatocytes and livers from male Sprague Dawley rats subjected to simulated in vivo HIRI. The results of the present study demonstrated that Parkin expression and mitochondrial autophagy were upregulated post-HIRI, leading to decreased hepatocyte death. Parkin knockdown suppresses the level of mitochondrial autophagy and promotes hepatocyte apoptosis by suppressing apoptosis regulator Bcl-2 function post-HIRI. In addition, Parkin deficiency alters cell cycle distribution and impairs DNA damage repair post-HIRI. In conclusion, Parkin facilitates mitochondrial autophagy and DNA damage repair, inhibits apoptosis, and modulates the cell cycle, leading to increased hepatocyte survival, demonstrating that Parkin may act as a protective regulatory factor post HIRI.

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“…PINK1 negatively regulated the PI3K/Akt/mTOR pathway [50], which might block mTOR-induced PP2A phosphorylation [51] whose suppression of PP2A activity [31]. In addition, PINK1 dysfunction decreased PP2A activity in in vitro of dopaminergic cell culture and the mouse striatum, suggesting that the protective activity of PINK1 could suppress the inactivation of PP2A [52].…”

Section: U N C O R R E C T E D a U T H O R P R O O Fmentioning

confidence: 99%

PTEN-Induced Putative Kinase 1 Dysfunction Accelerates Synucleinopathy

Nguyen

Kim

Lai

et al. 2022

JPD

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Background: Mutations in PTEN-induced putative kinase 1 (PINK1) cause autosomal recessive Parkinson’s disease (PD) and contribute to the risk of sporadic PD. However, the relationship between PD-related PINK1 mutations and alpha-synuclein (α-syn) aggregation—a main pathological component of PD—remains unexplored. Objective: To investigate whether α-syn pathology is exacerbated in the absence of PINK1 after α-syn preformed fibril (PFF) injection in a PD mouse model and its effects on neurodegeneration. Methods: In this study, 10-week-old Pink1 knockout (KO) and wildtype (WT) mice received stereotaxic unilateral striatal injection of recombinant mouse α-syn PFF. Then, α-syn pathology progression, inflammatory responses, and neurodegeneration were analyzed via immunohistochemistry, western blot analysis, and behavioral testing. Results: After PFF injection, the total α-syn levels significantly increased, and pathological α-syn was markedly aggregated in Pink1 KO mice compared with Pink1 WT mice. Then, earlier and more severe neuronal loss and motor deficits occurred. Moreover, compared with WT mice, Pink1 KO mice had evident microglial/astrocytic immunoreactivity and prolonged astrocytic activation, and a higher rate of protein phosphatase 2A phosphorylation, which might explain the greater α-syn aggravation and neuronal death. Conclusion: The loss of Pink1 function accelerated α-syn aggregate accumulation and glial activation, thereby leading to early and significant neurodegeneration and behavioral impairment in the PD mouse model. Therefore, our findings support the notion that PINK1 dysfunction increases the risk of synucleinopathy.

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Parkin, PINK1 and DJ1 as possible modulators of mTOR pathway in ganglioglioma

Abstract: It appears that mutations of parkin, PINK1 and DJ1 may result in the development of both neurodegeneration and tumors. Also, these proteins might be used as markers of disease, thus allowing better diagnosis and therapy.

Cited by 10 publications

References 49 publications

Iron Exposure and the Cellular Mechanisms Linked to Neuron Degeneration in Adult Mice

Iron Exposure and the Cellular Mechanisms Linked to Neuron Degeneration in Adult Mice

Parkin deficiency elevates hepatic ischemia/reperfusion injury accompanying decreased mitochondrial autophagy, increased apoptosis, impaired DNA damage repair and altered cell cycle distribution

PTEN-Induced Putative Kinase 1 Dysfunction Accelerates Synucleinopathy

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