MicroRNA-7 Protects Against Neurodegeneration Induced by α-Synuclein Preformed Fibrils in the Mouse Brain

Zhang, Jie; Zhao, Mengyuan; Yan, Run‐Tao; Liu, Jun; Maddila, Santhosh Chandar; Junn, Eunsung; Mouradian, M. Maral

doi:10.1007/s13311-021-01130-6

Cited by 12 publications

(13 citation statements)

References 64 publications

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“…In addition, non-coding RNAs (ncRNAs) can regulate many genes at the transcriptional level, despite not being translated into proteins. Their functions have been detected in the mitochondria, while ncRNAs such as microRNAs (miRNAs) ( Zhang et al, 2021 ), long non-coding RNAs ( Kopp et al, 2019 ), and some circular RNAs ( Shao and Chen, 2016 ) have been shown to play multiple roles in many of the underlying mechanisms of PD pathogenesis. Observations of various epigenetic changes in mtDNA have received considerable attention.…”

Section: Factors Affecting Mitochondrial Impairment In Sporadic Parki...mentioning

confidence: 99%

“…Further studies have suggested that the reduction in expression of miR-34b and miR-34c is related to the expression of DJ-1 and parkin, although the underlying mechanism is still unclear ( Polytarchou et al, 2020 ). According to reports, several miRNAs regulate the expression and accumulation of α-syn, such as miR-7, miR-34b/c, and miR-19a-3p ( Consales et al, 2018 ; Zhou et al, 2019 ; Zhang et al, 2021 ); their alterations may promote α-syn-mediated neurotoxicity. Abnormal expression of miRNA can be triggered by long-term environmental stressors, such as oxidative stress, toxins, or pathogens that induce both physiological and pathological stress.…”

Section: Mitochondrial Quality Control In Parkinson’s Diseasementioning

confidence: 99%

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Mitochondrial Dysfunction in Parkinson’s Disease: From Mechanistic Insights to Therapy

Gao

Yang²,

Gu³

et al. 2022

Front. Aging Neurosci.

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Parkinson’s disease (PD) is one of the most common neurodegenerative movement disorders worldwide. There are currently no cures or preventative treatments for PD. Emerging evidence indicates that mitochondrial dysfunction is closely associated with pathogenesis of sporadic and familial PD. Because dopaminergic neurons have high energy demand, cells affected by PD exhibit mitochondrial dysfunction that promotes the disease-defining the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The mitochondrion has a particularly important role as the cellular “powerhouse” of dopaminergic neurons. Therefore, mitochondria have become a promising therapeutic target for PD treatments. This review aims to describe mitochondrial dysfunction in the pathology of PD, outline the genes associated with familial PD and the factors related to sporadic PD, summarize current knowledge on mitochondrial quality control in PD, and give an overview of therapeutic strategies for targeting mitochondria in neuroprotective interventions in PD.

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Section: Factors Affecting Mitochondrial Impairment In Sporadic Parki...mentioning

confidence: 99%

Section: Mitochondrial Quality Control In Parkinson’s Diseasementioning

confidence: 99%

Mitochondrial Dysfunction in Parkinson’s Disease: From Mechanistic Insights to Therapy

Gao

Yang²,

Gu³

et al. 2022

Front. Aging Neurosci.

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“…Furthermore, MiRNA-7 also protects against oxidative stress by inhibiting the cytoplasmic inhibitory protein Kelch-like ECH-associated protein 1 (Keap1) ( Titze-de-Almeida and Titze-de-Almeida, 2018 ; Zhang et al, 2021 ). However, Keap1 is detected in physiological circumstances complexed with erythroid 2–related factor 2 (Nrf2) ( Zhang et al, 2021 ), a nuclear protein that regulates antioxidant gene expression. Keap1 inhibits the migration of Nrf2 to the cell nucleus ( Zhang et al, 2021 ).…”

Section: Therapeutic Approaches Involved In Genetic Regulations In Pa...mentioning

confidence: 99%

“…However, Keap1 is detected in physiological circumstances complexed with erythroid 2–related factor 2 (Nrf2) ( Zhang et al, 2021 ), a nuclear protein that regulates antioxidant gene expression. Keap1 inhibits the migration of Nrf2 to the cell nucleus ( Zhang et al, 2021 ). In this way, suppressing miRNA-7 over Keap1 will allow Nrf2 to move to the nucleus and activate genes that decrease oxidative stress.…”

Section: Therapeutic Approaches Involved In Genetic Regulations In Pa...mentioning

confidence: 99%

Recent developments in nucleic acid-based therapies for Parkinson’s disease: Current status, clinical potential, and future strategies

Pandey

Singh²

2022

Front. Pharmacol.

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Parkinson’s disease is the second most common progressive neurodegenerative disease diagnosed mainly based on clinical symptoms caused by loss of nigrostriatal dopaminergic neurons. Although currently available pharmacological therapies provide symptomatic relief, however, the disease continues to progress eventually leading to severe motor and cognitive decline and reduced quality of life. The hallmark pathology of Parkinson’s disease includes intraneuronal inclusions known as Lewy bodies and Lewy neurites, including fibrillar α-synuclein aggregates. These aggregates can progressively spread across synaptically connected brain regions leading to emergence of disease symptoms with time. The α-synuclein level is considered important in its fibrillization and aggregation. Nucleic acid therapeutics have recently been shown to be effective in treating various neurological diseases, raising the possibility of developing innovative molecular therapies for Parkinson’s disease. In this review, we have described the advancements in genetic dysregulations in Parkinson’s disease along with the disease-modifying strategies involved in genetic regulation with particular focus on downregulation of α-synuclein gene using various novel technologies, notably antisense oligonucleotides, microRNA, short interfering RNA, short hairpin RNAs, DNA aptamers, and gene therapy of vector-assisted delivery system-based therapeutics. In addition, the current status of preclinical and clinical development for nucleic acid-based therapies for Parkinson’s disease have also been discussed along with their limitations and opportunities.

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“…However, according to a recent study, a brain-enriched miRNA miR-7 that downregulates alpha-synuclein production via interaction with the 3′ untranslated region of the encoding mRNA [ 48 ] ameliorates the pathology triggered by the inoculation of alpha-synuclein preformed fibrils (PFF) into mouse striatum. The adeno-associated virus 1-based vector (AAV-miR-7) was used for delivery, and the resulting expression of miR-7 in the striatum reduced the levels of both monomeric, including phosphorylated, and aggregated alpha-synuclein, attenuated neurodegeneration, neuroinflammation, and behavioral deficits that are typical for this mouse model of alpha-synucleinopathy [ 49 ].…”

Section: Post-transcriptional Targeting Of Alpha-synuclein Productionmentioning

confidence: 99%

Toward a Disease-Modifying Therapy of Alpha-Synucleinopathies: New Molecules and New Approaches Came into the Limelight

2021

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The accumulation of the various products of alpha-synuclein aggregation has been associated with the etiology and pathogenesis of several neurodegenerative conditions, including both familial and sporadic forms of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). It is now well established that the aggregation and spread of alpha-synuclein aggregation pathology activate numerous pathogenic mechanisms that contribute to neurodegeneration and, ultimately, to disease progression. Therefore, the development of a safe and effective disease-modifying therapy that limits or prevents the accumulation of the toxic intermediate products of alpha-synuclein aggregation and the spread of alpha-synuclein aggregation pathology could provide significant positive clinical outcomes in PD/DLB cohorts. It has been suggested that this goal can be achieved by reducing the intracellular and/or extracellular levels of monomeric and already aggregated alpha-synuclein. The principal aim of this review is to critically evaluate the potential of therapeutic strategies that target the post-transcriptional steps of alpha-synuclein production and immunotherapy-based approaches to alpha-synuclein degradation in PD/DLB patients. Strategies aimed at the downregulation of alpha-synuclein production are at an early preclinical stage of drug development and, although they have shown promise in animal models of alpha-synuclein aggregation, many limitations need to be resolved before in-human clinical trials can be seriously considered. In contrast, many strategies aimed at the degradation of alpha-synuclein using immunotherapeutic approaches are at a more advanced stage of development, with some in-human Phase II clinical trials currently in progress. Translational barriers for both strategies include the limitations of alpha-synuclein aggregation models, poor understanding of the therapeutic window for the alpha-synuclein knockdown, and variability in alpha-synuclein pathology across patient cohorts. Overcoming such barriers should be the main focus of further studies. However, it is already clear that these strategies do have the potential to achieve a disease-modifying effect in PD and DLB.

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MicroRNA-7 Protects Against Neurodegeneration Induced by α-Synuclein Preformed Fibrils in the Mouse Brain

Cited by 12 publications

References 64 publications

Mitochondrial Dysfunction in Parkinson’s Disease: From Mechanistic Insights to Therapy

Mitochondrial Dysfunction in Parkinson’s Disease: From Mechanistic Insights to Therapy

Recent developments in nucleic acid-based therapies for Parkinson’s disease: Current status, clinical potential, and future strategies

Toward a Disease-Modifying Therapy of Alpha-Synucleinopathies: New Molecules and New Approaches Came into the Limelight

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