The role of mitochondrial disturbances in Alzheimer, Parkinson and Huntington diseases

Carvalho, Cristina; Correia, Sónia C.; Cardoso, Susana M.; Plácido, Ana I.; Candeias, Emanuel; Duarte, Ana I.; Moreira, Paula I.

doi:10.1586/14737175.2015.1058160

Cited by 39 publications

(26 citation statements)

References 252 publications

(154 reference statements)

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“…These results suggest that increased translocation of Drp-1 in the mitochondria is involved in BPA-mediated neurotoxicity. (1,25,47). We hypothesized whether increased mitochondrial fragmentation and cristae depletion by BPA leads to accumulation of defective mitochondria and mitochondrial dysfunction.…”

Section: Drp-1 Is Involved In the Regulation Of Bpa-induced Mitochondmentioning

confidence: 99%

Dynamin-related Protein 1 Inhibition Mitigates Bisphenol A-mediated Alterations in Mitochondrial Dynamics and Neural Stem Cell Proliferation and Differentiation

Agarwal

Yadav

Tiwari

et al. 2016

Journal of Biological Chemistry

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The regulatory dynamics of mitochondria comprises well orchestrated distribution and mitochondrial turnover to maintain the mitochondrial circuitry and homeostasis inside the cells. Several pieces of evidence suggested impaired mitochondrial dynamics and its association with the pathogenesis of neurodegenerative disorders. We found that chronic exposure of synthetic xenoestrogen bisphenol A (BPA), a component of consumer plastic products, impaired autophagy-mediated mitochondrial turnover, leading to increased oxidative stress, mitochondrial fragmentation, and apoptosis in hippocampal neural stem cells (NSCs). It also inhibited hippocampal derived NSC proliferation and differentiation, as evident by the decreased number of BrdU-and ␤-III tubulin-positive cells. All these effects were reversed by the inhibition of oxidative stress using N-acetyl cysteine. BPA up-regulated the levels of Drp-1 (dynamin-related protein 1) and enhanced its mitochondrial translocation, with no effect on Fis-1, Mfn-1, Mfn-2, and Opa-1 in vitro and in the hippocampus. Moreover, transmission electron microscopy studies suggested increased mitochondrial fission and accumulation of fragmented mitochondria and decreased elongated mitochondria in the hippocampus of the rat brain. Impaired mitochondrial dynamics by BPA resulted in increased reactive oxygen species and malondialdehyde levels, disruption of mitochondrial membrane potential, and ATP decline. Pharmacological (Mdivi-1) and genetic (Drp-1siRNA) inhibition of Drp-1 reversed BPA-induced mitochondrial dysfunctions, fragmentation, and apoptosis. Interestingly, BPAmediated inhibitory effects on NSC proliferation and neuronal differentiations were also mitigated by Drp-1 inhibition. On the other hand, Drp-1 inhibition blocked BPA-mediated Drp-1 translocation, leading to decreased apoptosis of NSC. Overall, our studies implicate Drp-1 as a potential therapeutic target against BPA-mediated impaired mitochondrial dynamics and neurodegeneration in the hippocampus.

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Section: Drp-1 Is Involved In the Regulation Of Bpa-induced Mitochondmentioning

confidence: 99%

Dynamin-related Protein 1 Inhibition Mitigates Bisphenol A-mediated Alterations in Mitochondrial Dynamics and Neural Stem Cell Proliferation and Differentiation

Agarwal

Yadav

Tiwari

et al. 2016

Journal of Biological Chemistry

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“…While neurodegenerative diseases are clinically diverse, depending on the group of neurons affected, these diseases share some underlying impairments. Common compromised processes are mitochondrial function upon oxidative stress, RNA function and metabolism, the UPS system, and the altered solubility of specific disease-associated proteins (14, 105, 126). The UPS system is being extensively investigated in this context, and failure of proper protein degradation plays an important part in the pathogenesis of neurodegenerative diseases (149).…”

Section: Sumoylation Regulates Protein Aggregation In Neurodegeneratimentioning

confidence: 99%

Ubiquitin-dependent and independent roles of SUMO in proteostasis

Liebelt

Vertegaal

2016

American Journal of Physiology-Cell Physiology

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Cellular proteomes are continuously undergoing alterations as a result of new production of proteins, protein folding, and degradation of proteins. The proper equilibrium of these processes is known as proteostasis, implying that proteomes are in homeostasis. Stress conditions can affect proteostasis due to the accumulation of misfolded proteins as a result of overloading the degradation machinery. Proteostasis is affected in neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, and multiple polyglutamine disorders including Huntington's disease. Owing to a lack of proteostasis, neuronal cells build up toxic protein aggregates in these diseases. Here, we review the role of the ubiquitin-like posttranslational modification SUMO in proteostasis. SUMO alone contributes to protein homeostasis by influencing protein signaling or solubility. However, the main contribution of SUMO to proteostasis is the ability to cooperate with, complement, and balance the ubiquitin-proteasome system at multiple levels. We discuss the identification of enzymes involved in the interplay between SUMO and ubiquitin, exploring the complexity of this crosstalk which regulates proteostasis. These enzymes include SUMO-targeted ubiquitin ligases and ubiquitin proteases counteracting these ligases. Additionally, we review the role of SUMO in brain-related diseases, where SUMO is primarily investigated because of its role during formation of aggregates, either independently or in cooperation with ubiquitin. Detailed understanding of the role of SUMO in these diseases could lead to novel treatment options.

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“…These diseases share the property that mitochondria (MT) do not keep up with the energy demands of the cell (Arun et al, 2016). However, AD, PD, and HD display region-specific cell death (Carvalho et al, 2015), and even within those regions, only select cell types are targeted (Reiner et al, 1988). In HD, for example, the toxic disease-causing protein is ubiquitously expressed, but initially, only the medium spiny neurons in the striatum (STR) are targeted for death (Arun et al, 2016; Carvalho et al, 2015; Reiner et al, 1988; Ross et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

“…However, AD, PD, and HD display region-specific cell death (Carvalho et al, 2015), and even within those regions, only select cell types are targeted (Reiner et al, 1988). In HD, for example, the toxic disease-causing protein is ubiquitously expressed, but initially, only the medium spiny neurons in the striatum (STR) are targeted for death (Arun et al, 2016; Carvalho et al, 2015; Reiner et al, 1988; Ross et al, 2017). Despite significant effort, however, researchers have yet to discover whether mitochondrial dysfunction is a cause of toxicity or a mechanism (reviewed in Brustovetsky, 2016; Liot et al, 2017; Polyzos and McMurray, 2017).…”

Section: Introductionmentioning

confidence: 99%

Metabolic Reprogramming in Astrocytes Distinguishes Region-Specific Neuronal Susceptibility in Huntington Mice

et al. 2019

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SUMMARY The basis for region-specific neuronal toxicity in Huntington disease is unknown. Here, we show that region-specific neuronal vulnerability is a substrate-driven response in astrocytes. Glucose is low in HdhQ(150/150) animals, and astrocytes in each brain region adapt by metabolically reprogramming their mitochondria to use endogenous, non-glycolytic metabolites as an alternative fuel. Each region is characterized by distinct metabolic pools, and astrocytes adapt accordingly. The vulnerable striatum is enriched in fatty acids, and mitochondria reprogram by oxidizing them as an energy source but at the cost of escalating reactive oxygen species (ROS)-induced damage. The cerebellum is replete with amino acids, which are precursors for glucose regeneration through the pentose phosphate shunt or gluconeogenesis pathways. ROS is not elevated, and this region sustains little damage. While mhtt expression imposes disease stress throughout the brain, sensitivity or resistance arises from an adaptive stress response, which is inherently region specific. Metabolic reprogramming may have relevance to other diseases.

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The role of mitochondrial disturbances in Alzheimer, Parkinson and Huntington diseases

Cited by 39 publications

References 252 publications

Dynamin-related Protein 1 Inhibition Mitigates Bisphenol A-mediated Alterations in Mitochondrial Dynamics and Neural Stem Cell Proliferation and Differentiation

Dynamin-related Protein 1 Inhibition Mitigates Bisphenol A-mediated Alterations in Mitochondrial Dynamics and Neural Stem Cell Proliferation and Differentiation

Ubiquitin-dependent and independent roles of SUMO in proteostasis

Metabolic Reprogramming in Astrocytes Distinguishes Region-Specific Neuronal Susceptibility in Huntington Mice

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