Protein Misfolding and Aggregation: The Relatedness between Parkinson’s Disease and Hepatic Endoplasmic Reticulum Storage Disorders

Padilla-Godínez, Francisco J.; Ramos-Acevedo, Rodrigo; Martínez-Becerril, Hilda Angélica; Bernal-Conde, Luis Daniel; Garrido-Figueroa, Jerónimo F; Hiriart, Marcia; Hernández-López, Adriana; Argüero‐Sánchez, Rubén; Callea, Francesco; Guerra-Crespo, Magdalena

doi:10.3390/ijms222212467

Cited by 11 publications

(7 citation statements)

References 259 publications

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“…Nonetheless, when the capacity of UPR to maintain proteostasis is overwhelmed, cells activate the control of cell death by apoptosis [ 60 ]. In this regard, α-syn overexpression correlates with chronic activation of multiple pathways of the UPR system and ER stress-mediated apoptosis [ 61 ], ultimately leading to inflammation and neurodegeneration. Indeed, ER dysfunction has been positioned as an early component of PD pathogenesis [ 62 , 63 ].…”

Section: Current Knowledge Of Parkinson’s Disease’s Neuropathologymentioning

confidence: 99%

Nanomedicine in the Face of Parkinson’s Disease: From Drug Delivery Systems to Nanozymes

Padilla-Godínez

Ruiz-Ortega

Guerra-Crespo

2022

Cells

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The complexity and overall burden of Parkinson’s disease (PD) require new pharmacological approaches to counteract the symptomatology while reducing the progressive neurodegeneration of affected dopaminergic neurons. Since the pathophysiological signature of PD is characterized by the loss of physiological levels of dopamine (DA) and the misfolding and aggregation of the alpha-synuclein (α-syn) protein, new proposals seek to restore the lost DA and inhibit the progressive damage derived from pathological α-syn and its impact in terms of oxidative stress. In this line, nanomedicine (the medical application of nanotechnology) has achieved significant advances in the development of nanocarriers capable of transporting and delivering basal state DA in a controlled manner in the tissues of interest, as well as highly selective catalytic nanostructures with enzyme-like properties for the elimination of reactive oxygen species (responsible for oxidative stress) and the proteolysis of misfolded proteins. Although some of these proposals remain in their early stages, the deepening of our knowledge concerning the pathological processes of PD and the advances in nanomedicine could endow for the development of potential treatments for this still incurable condition. Therefore, in this paper, we offer: (i) a brief summary of the most recent findings concerning the physiology of motor regulation and (ii) the molecular neuropathological processes associated with PD, together with (iii) a recapitulation of the current progress in controlled DA release by nanocarriers and (iv) the design of nanozymes, catalytic nanostructures with oxidoreductase-, chaperon, and protease-like properties. Finally, we conclude by describing the prospects and knowledge gaps to overcome and consider as research into nanotherapies for PD continues, especially when clinical translations take place.

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Section: Current Knowledge Of Parkinson’s Disease’s Neuropathologymentioning

confidence: 99%

Nanomedicine in the Face of Parkinson’s Disease: From Drug Delivery Systems to Nanozymes

Padilla-Godínez

Ruiz-Ortega

Guerra-Crespo

2022

Cells

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“…Proteotoxicity results from misfolded or damaged proteins being transformed into non-native configurations, causing their dysfunctions and negatively affecting cellular homeostasis . Furthermore, misfolded proteins can polymerize, leading to their aggregations that are the root causes of several neurodegenerative diseases, such as Parkinson’s disease (PD), Alzheimer’s disease (AD), amyotrophic lateral sclerosis, and Huntington’s disease . Among these, PD is the second most common neurodegenerative disorder worldwide, characterized by the degeneration of dopaminergic (DAergic) neurons due to the formation of α-synuclein aggregation in the forms of Lewy bodies within these neurons .…”

Section: Introductionmentioning

confidence: 99%

2-Butoxytetrahydrofuran, Isolated from Holothuria scabra, Attenuates Aggregative and Oxidative Properties of α-Synuclein and Alleviates Its Toxicity in a Transgenic Caenorhabditis elegans Model of Parkinson’s Disease

Promtang,

Sanguanphun,

Chalorak

et al. 2024

ACS Chem. Neurosci.

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Aggregative α-synuclein and incurring oxidative stress are pivotal cascading events, leading to dopaminergic (DAergic) neuronal loss and contributing to clinical manifestations of Parkinson's disease (PD). Our previous study demonstrated that 2-butoxytetrahydrofuran (2-BTHF), isolated from Holothuria scabra (H. scabra), could inhibit amyloid-β aggregation and its ensuing toxicity, which leads to Alzheimer's disease. In the present study, we found that 2-BTHF also attenuated the aggregative and oxidative activities of α-synuclein and lessened its toxicity in a transgenic Caenorhabditis elegans (C. elegans) PD model. Such worms treated with 100 μM of 2-BTHF showed substantial reductions in αsynuclein accumulation and DAergic neurodegeneration. Mechanistically, 2-BTHF, at this concentration, significantly decreased aggregation of monomeric α-synuclein and restored locomotion and dopamine-dependent behaviors. Molecular docking exhibited potential bindings of 2-BTHF to HSF-1 and DAF-16 transcription factors. Additionally, 2-BTHF significantly increased the mRNA transcripts of genes encoding proteins involved in proteostasis, including the molecular chaperones hsp-16.2 and hsp-16.49, the ubiquitination/SUMOylation-related ubc-9 gene, and the autophagy-related genes atg-7 and lgg-1. Transcriptomic profiling revealed an additional mechanism of 2-BTHF in α-synuclein-expressing worms, which showed upregulation of PPAR signaling cascades that mediated fatty acid metabolism. 2-BTHF significantly restored lipid deposition, upregulated the fat-7 gene, and enhanced gcs-1-mediated glutathione synthesis in the C. elegans PD model. Taken together, this study demonstrated that 2-BTHF could abrogate aggregative and oxidative properties of α-synuclein and attenuate its toxicity, thus providing a possible therapeutic application for the treatment of α-synuclein-induced PD.

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“…Non-motor manifestations in PD, like cognitive dysfunction, sleep disorders, olfactory dysfunction, gastrointestinal disorders, and visual disturbances, represent the primary source of PD burden [ 72 ]. These manifestations usually occur many years before the development and progression of motor symptoms.…”

Section: Introductionmentioning

confidence: 99%

Role of GABA pathway in motor and non-motor symptoms in Parkinson's disease: a bidirectional circuit

Alharbi,

Al-kuraishy,

Al-Gareeb

et al. 2024

Eur J Med Res

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Parkinson's disease (PD) is a progressive neurodegenerative disease as a result of the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The fundamental features of PD are motor and non-motor symptoms. PD symptoms develop due to the disruption of dopaminergic neurotransmitters and other neurotransmitters such as γ-aminobutyric acid (GABA). The potential role of GABA in PD neuropathology concerning the motor and non-motor symptoms of PD was not precisely discussed. Therefore, this review intended to illustrate the possible role of GABA in PD neuropathology regarding motor and non-motor symptoms. The GABA pathway is essential in regulating the inhibitory tone to prevent excessive stimulation of the cerebral cortex. Degeneration of dopaminergic neurons in PD is linked with reducing GABAergic neurotransmission. Decreasing GABA activity promotes mitochondrial dysfunction and oxidative stress, which are highly related to PD neuropathology. Hence, restoring GABA activity by GABA agonists may attenuate the progression of PD motor symptoms. Therefore, dysregulation of GABAergic neurons in the SNpc contributes to developing PD motor symptoms. Besides, PD non-motor symptoms are also related to the dysfunction of the GABAergic pathway, and amelioration of this pathway may reduce PD non-motor symptoms. In conclusion, the deregulation of the GABAergic pathway in PD might be intricate in developing motor and non-motor symptoms. Improving this pathway might be a novel, beneficial approach to control PD symptoms.

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Protein Misfolding and Aggregation: The Relatedness between Parkinson’s Disease and Hepatic Endoplasmic Reticulum Storage Disorders

Cited by 11 publications

References 259 publications

Nanomedicine in the Face of Parkinson’s Disease: From Drug Delivery Systems to Nanozymes

Nanomedicine in the Face of Parkinson’s Disease: From Drug Delivery Systems to Nanozymes

2-Butoxytetrahydrofuran, Isolated from Holothuria scabra, Attenuates Aggregative and Oxidative Properties of α-Synuclein and Alleviates Its Toxicity in a Transgenic Caenorhabditis elegans Model of Parkinson’s Disease

Role of GABA pathway in motor and non-motor symptoms in Parkinson's disease: a bidirectional circuit

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