Mitochondrial dysfunction in Parkinson’s disease – a key disease hallmark with therapeutic potential

Henrich, Martin T.; Oertel, Wolfgang H.; Surmeier, D. James; Geibl, Fanni F.

doi:10.1186/s13024-023-00676-7

Cited by 51 publications

(22 citation statements)

References 280 publications

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“…MPTP inhibits Complex I of the mitochondrial electron transport chain. Evidence that mitochondrial perturbation is a driver of synaptic dysfunction has been previously reported for AD 75 , PD 76,77 , ALS 78,79 , and HD 80,81 . Our main results recapitulate the common deficits following MPTP treatment such as activation of reactive oxygen species pathways, impaired oxidative phosphorylation, ATP loss, defective mitochondrial homeostasis, or the unfolded protein response.…”

Section: Panx1a Integrates Cellular Homeostasis With Mitochondrial He...mentioning

confidence: 72%

Panx1 Ablation Aggravates Oxidative Stress and Cell Death by Altering AMPK/mTOR signaling Pathways and the Composition of Synapses in the Zebrafish

Zoidl,

Safarian,

Zoidl

et al. 2024

Preprint

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Pannexin-1 (Panx1) channels have garnered attention for their implications in neurodegeneration, potentially with a role in mediating the delicate balance between cell death and survival. However, a comprehensive understanding of the underlying molecular and cellular mechanisms remains elusive, and whether Panx1 exhibits dual protective and toxic roles throughout the lifespan remains to be determined. To address these gaps, we focused on early-life changes in zebrafish larvae with impaired Panx1a function subjected to acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. We demonstrate that a single four-hour exposure to MPTP induces substantial alterations in locomotor behavior, the transcriptome, and local field potentials within the ascending visual pathway. KEGG pathway analysis underscored MPTP's regulatory influence on neurodegeneration; here the differential expression of biomarkers for Alzheimer's, Parkinson's, Amyotrophic Lateral Sclerosis (ALS), and Huntington's disease, suggested a protective role of Panx1a ablation. However, the potential beneficial impact of targeting Panx1a is superseded by the deregulation of oxidative phosphorylation, glycolysis, ROS, hypoxia, unfolded protein response pathways, and reduced extracellular ATP. Notably, these changes correlate with a loss of synaptic neurotransmitter receptor and ion channel/transaporter expression and the differential expression of mTORC1, autophagy, and apoptosis signaling pathways. The resultant cell death was demonstrated by acridine orange dye uptake and in-vivo imaging, with a pronounced loss of cells observed in the pallium and tectum regions. Dual recordings of local field potentials across the optic tectum and pallium demonstrate Panx1a's involvement in modulating local neuronal networks. Collectively, our results shed light on the impacts of acute MPTP treatment on locomotor behavior, transcriptomic shifts, metabolic disturbances, and the pivotal role of Panx1a in neurodegeneration and cell death. These insights enhance our comprehension of the intricate molecular and cellular mechanisms underpinning neurodegeneration, with implications for potential therapeutic strategies targeting Panx1 channels in the context of neuroinflammatory pathologies.

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Section: Panx1a Integrates Cellular Homeostasis With Mitochondrial He...mentioning

confidence: 72%

Panx1 Ablation Aggravates Oxidative Stress and Cell Death by Altering AMPK/mTOR signaling Pathways and the Composition of Synapses in the Zebrafish

Zoidl,

Safarian,

Zoidl

et al. 2024

Preprint

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“…The precise targets for the action of USP14 on mitochondria related to oxidative stress - 26S proteasome crosstalk remains to be studied. α-Syn aggregates can disrupt mitochondrial functions and result in oxidative stress in midbrain dopaminergic neurons susceptible to degeneration in PD 9, 52 . More focus has recently been on understanding pS129 α-syn and its role in PD.…”

Section: Discussionmentioning

confidence: 99%

“…α-Syn accumulates in intracellular aggregates termed Lewy bodies that form within PD-susceptible midbrain dopaminergic neurons. This is accompanied disturbed protein handling, mitochondria defects, increased oxidative stress-associated damage, and ER stress 9, 10 . The mechanisms by which misfolded α-syn are elevated in PD are not fully understood but defects in proteasome and autophagy are proposed to contribute to the disease.…”

Section: Introductionmentioning

confidence: 99%

USP14 regulates pS129 α-synuclein levels and oxidative stress in human SH-SY5Y dopaminergic cells

Srinivasan,

Soliymani,

Ivanova

et al. 2024

Preprint

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Ubiquitin specific protease-14 (USP14) is critical for controlling protein homeostasis disturbed in human disorders like Parkinson′s disease (PD). Here we investigated the role of USP14 in regulating proteasome and autophagy pathways, and their influence on α-synuclein (α-syn) degradation. Data showed that α-syn and phosphorylated serine129 α-syn (pS129 α-syn) were elevated in USP14 gene deleted SH-SY5Y dopaminergic cells with concomitant reduction in proteasome activity. Inhibition of proteasomes using MG132 particularly elevated pS129 α-syn in these cells, but the levels were not influenced by inhibiting autophagy using chloroquine. In contrast, autophagy and the CLEAR (Coordinated Lysosomal Expression and Regulation) pathways were elevated in USP14 lacking cells with an upregulation of the transcription factor TFEB. USP14-ablated cells also exhibited increases in reactive oxidative species (ROS) and elongation of mitochondria. The addition of N-Acetylcysteine amide (NACA) to counteract oxidative stress, reduced pS129 α-syn and α-syn levels in USP14 deficient cells. Phospho-proteomic analyses revealed that USP14 is phosphorylated at S143 affecting its function and structure as shown by molecular modeling, and protein interaction studies. Re-expression of wild-type and the phospho-mimetic S143D-USP14 mutant decreased ROS, pS129 α-syn, and α-syn in USP14 lacking cells. These results demonstrate that pS129 α-syn levels are sensitive to oxidative stress in SH-SY5Y dopaminergic cells. USP14 by stimulating the proteasome activity and reducing oxidative stress is a promising factor for targeting α-syn and its pathogenic variants in PD.

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“…The mechanism has been utilized to prevent cancer-related diseases, cardiovascular diseases, neurodegenerative conditions, and metabolic disorders ( Naren et al, 2023 ). Oxidative impairment refers to a disequilibrium between ROS production and the cell’s ability to repair damage ( Henrich et al, 2023 ). It can contribute to cellular dysfunction and tissue damage through multiple mechanisms, which include direct oxidative damage to biomolecules, inflammatory pathway activation, cellular signaling disruption, and mitochondrial function impairment ( Martemucci et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

SIRT1/P53 in retinal pigment epithelial cells in diabetic retinopathy: a gene co-expression analysis and He-Ying-Qing-Re formula treatment

Zhang,

Wu,

Wang

et al. 2024

Front. Mol. Biosci.

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Objective:Diabetic retinopathy (DR) is a severe diabetic complication that leads to severe visual impairment or blindness. He-Ying-Qing-Re formula (HF), a traditional Chinese medicinal concoction, has been identified as an efficient therapy for DR with retinal vascular dysfunction for decades and has been experimentally reported to ameliorate retinal conditions in diabetic mice. This study endeavors to explore the therapeutic potential of HF with key ingredients in DR and its underlying novel mechanisms.Methods:Co-expression gene modules and hub genes were calculated by weighted gene co-expression network analysis (WGCNA) based on transcriptome sequencing data from high-glucose-treated adult retinal pigment epithelial cell line-19 (ARPE-19). The chromatographic fingerprint of HF was established by ultra-performance liquid chromatography coupled with high-resolution mass spectrometry (UPLC-Q-TOF-MS). The molecular affinity of the herbal compound was measured by molecular docking. Reactive oxygen species (ROS) was measured by a DCFDA/H2DCFDA assay. Apoptosis was detected using the TUNEL Assay Kit, while ELISA, Western blot, and real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) were used for detecting the cytokine, protein, and mRNA expressions, respectively.Results:Key compounds in HF were identified as luteolin, paeoniflorin, and nobiletin. For WGCNA, ME-salmon (“protein deacetylation”) was negatively correlated with ME-purple (“oxidative impairment”) in high-glucose-treated ARPE-19. Luteolin has a high affinity for SIRT1 and P53, as indicated by molecular docking. Luteolin has a hypoglycemic effect on type I diabetic mice. Moreover, HF and luteolin suppress oxidative stress production (ROS and MDA), inflammatory factor expression (IL-6, TNF-α, IL1-β, and MCP-1), and apoptosis, as shown in the in vivo and in vitro experiments. Concurrently, treatment with HF and luteolin led to an upregulation of SIRT1 and a corresponding downregulation of P53.Conclusion:Using HF and its active compound luteolin as therapeutic agents offers a promising approach to diabetic retinopathy treatment. It primarily suppressed protein acetylation and oxidative stress via the SIRT1/P53 pathway in retinal pigment epithelial cells.

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Mitochondrial dysfunction in Parkinson’s disease – a key disease hallmark with therapeutic potential

Cited by 51 publications

References 280 publications

Panx1 Ablation Aggravates Oxidative Stress and Cell Death by Altering AMPK/mTOR signaling Pathways and the Composition of Synapses in the Zebrafish

Panx1 Ablation Aggravates Oxidative Stress and Cell Death by Altering AMPK/mTOR signaling Pathways and the Composition of Synapses in the Zebrafish

USP14 regulates pS129 α-synuclein levels and oxidative stress in human SH-SY5Y dopaminergic cells

SIRT1/P53 in retinal pigment epithelial cells in diabetic retinopathy: a gene co-expression analysis and He-Ying-Qing-Re formula treatment

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