The Role of Mitochondrial Genes in Neurodegenerative Disorders

Kumar, Rajesh; Harila, Seetha; Parambi, Della Grace Thomas; Kanthlal, S.K.; Ma, Rahman; Alexiou, Athanasios; Batiha, Gaber El‐Saber; Mathew, Bijo

doi:10.2174/1570159x19666210908163839

Cited by 11 publications

(9 citation statements)

References 119 publications

(152 reference statements)

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“…If a certain heteroplasmy threshold is exceeded, mitochondrial homeostasis can be impaired, subsequently leading to impairments similar to those seen in primary mitochondrial disease and ultimately to cell death [40] (see Figure 2). There is strong experimental evidence that genetic variations in mtDNA increase with age, which also translates to our pathophysiological understanding of the development of neurodegenerative diseases [41]. It has also been shown that the mtDNA mutation rate accelerates with higher age which is especially relevant to postmitotic neurons [42].…”

Section: A Primer On Mitochondrial Biologymentioning

confidence: 99%

“…Even though mtDNA alterations have been observed in physiological aging, the increased amount of mtDNA rearrangements and deletions in PD patients suggest a certain disease specificity [58]. Accordingly, SN-related mtDNA deletions and copy number variations are more common in PD than in patients with other neurodegenerative diseases (e.g., Alzheimer's disease (AD)) [41]. PD patients are thus more likely to accumulate mtDNA mutations particularly in dopaminergic neurons.…”

Section: The Role Of Mitochondrial Dna Deletions and Copy Number Variations In Pdmentioning

confidence: 99%

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Gene Therapeutic Approaches for the Treatment of Mitochondrial Dysfunction in Parkinson’s Disease

Prasuhn

Brüggemann

2021

Preprint

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Background. Mitochondrial dysfunction has been identified as a pathophysiological hallmark of disease onset and progression in patients with Parkinsonian disorders. Besides the overall emergence of gene therapies in treating these patients, this highly relevant molecular concept has not yet been defined as a target for gene therapeutic approaches. Methods. This narrative review will discuss the experimental evidence suggesting mitochondrial dysfunction as a viable treatment target in patients with monogenic and idiopathic Parkinson’s disease. In addition, we will focus on general treatment strategies and crucial challenges which need to be overcome. Results. Our current understanding of mitochondrial biology in parkinsonian disorders opens up the avenue for viable treatment strategies in Parkinsonian disorders. Insights can be obtained from primary mitochondrial diseases. However, substantial knowledge gaps and unique challenges of mitochondria-targeted gene therapies need to be addressed to provide innovative treatments in the future. Conclusions. Mitochondria-targeted gene therapies are a potential strategy to improve an important primary disease mechanism in Parkinsonian disorders. However, further studies are needed to address the unique design challenges for mitochondria-targeted gene therapies.

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Section: A Primer On Mitochondrial Biologymentioning

confidence: 99%

Section: The Role Of Mitochondrial Dna Deletions and Copy Number Variations In Pdmentioning

confidence: 99%

Gene Therapeutic Approaches for the Treatment of Mitochondrial Dysfunction in Parkinson’s Disease

Prasuhn

Brüggemann

2021

Preprint

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“…High rates of mutations and mitochondrial damage have been documented in the context of AiN 85,86 and numerous neurodegenerative diseases. 87 Due to its experimental flexibility, advanced and wellcharacterized neurocircuitry, and the availability of an unmatched genetic toolbox, the fruit fly is widely used as (1) a model for neurodegenerative diseases; (2) for toxicologic studies; and (3) for genetic studies and can be arguably considered the ideal model to test the hypothesis that AiN is a quantitative trait. Two models were used to explore the pharmacogenomics of the interactions of isoflurane with "fragile" brains: (1) the brain affected by neurodegeneration using a fly model of LS and (2) the injured brain using a fly Traumatic Brain Injury (TBI) model.…”

Section: Genetic Determinants Of Collateral Anesthetic Pharmacodynamicsmentioning

confidence: 99%

A primordial target: Mitochondria mediate both primary and collateral anesthetic effects of volatile anesthetics

Perouansky

Johnson-Schlitz

Sedensky

et al. 2023

Exp Biol Med (Maywood)

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One of the unsolved mysteries of medicine is how do volatile anesthetics (VAs) cause a patient to reversibly lose consciousness. In addition, identifying mechanisms for the collateral effects of VAs, including anesthetic-induced neurotoxicity (AiN) and anesthetic preconditioning (AP), has proven challenging. Multiple classes of molecules (lipids, proteins, and water) have been considered as potential VA targets, but recently proteins have received the most attention. Studies targeting neuronal receptors or ion channels had limited success in identifying the critical targets of VAs mediating either the phenotype of “anesthesia” or their collateral effects. Recent studies in both nematodes and fruit flies may provide a paradigm shift by suggesting that mitochondria may harbor the upstream molecular switch activating both primary and collateral effects. The disruption of a specific step of electron transfer within the mitochondrion causes hypersensitivity to VAs, from nematodes to Drosophila and to humans, while also modulating the sensitivity to collateral effects. The downstream effects from mitochondrial inhibition are potentially legion, but inhibition of presynaptic neurotransmitter cycling appears to be specifically sensitive to the mitochondrial effects. These findings are perhaps of even broader interest since two recent reports indicate that mitochondrial damage may well underlie neurotoxic and neuroprotective effects of VAs in the central nervous system (CNS). It is, therefore, important to understand how anesthetics interact with mitochondria to affect CNS function, not just for the desired facets of general anesthesia but also for significant collateral effects, both harmful and beneficial. A tantalizing possibility exists that both the primary (anesthesia) and secondary (AiN, AP) mechanisms may at least partially overlap in the mitochondrial electron transport chain (ETC).

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“…Neurodegenerative disorders characterized by a gradual reduction of nerve cell functions or structure that may lead to neuron death. Neurodegenerative diseases included Huntington's disease (HD), Parkinson's disease (PD),Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) [1]. These disorders are considered incurable, and they cause a progressive decline in health to the point that neurons die.…”

Section: Introductionmentioning

confidence: 99%

Alzheimer's Disease and the Possible Role of Vitamin D

Azhari

2022

JAMMR

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Alzheimer's disease (AD) is a neurological illness that causes dementia. Despite the enormous global economic cost and impact on patients' immediate family members, there is no definitive cure, necessitating the development of improved therapeutic options. While memory and cognition are significantly impaired with (AD), the actual cause remains unknown. Among well-known hypotheses used to explain AD pathophysiology is Amyloid (A β) plaque development and aggregation hypothesis. There are now five FDA-approved medications that are used as therapy alternatives. All medications are used to treat symptoms of (AD.) So, disease modifying treatments that target the AD pathological changes, are required. Those treatments may targeting suppression of the pathogenesis pathways. Vitamin D is generated in human epithelial cells through the photochemical formation and is also obtained through dietary resources. Calcium homeostasis and bone metabolism are two of the most well-known vitamin D impacts. Aside from that, non-traditional vitamin D benefits have recently acquired popularity. Vitamin D regulates the growth and activities of the central nervous system, which is an important but less understood function of the vitamin. Vitamin D's neuroprotective properties are associated with its effects on neurotrophin creation and secretion, neuromodulator synthesis, intracellular calcium homeostasis, and avoidance of oxidative nerve damage. The protective and therapeutic effects of vitamin D on neurodegenerative diseases are not intensively investigated In this review, a comprehensive approach to understanding the pathogenesis of AD and the possible role of vitamin D in the protection and therapeutic of AD were addressed.

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The Role of Mitochondrial Genes in Neurodegenerative Disorders

Cited by 11 publications

References 119 publications

Gene Therapeutic Approaches for the Treatment of Mitochondrial Dysfunction in Parkinson’s Disease

Gene Therapeutic Approaches for the Treatment of Mitochondrial Dysfunction in Parkinson’s Disease

A primordial target: Mitochondria mediate both primary and collateral anesthetic effects of volatile anesthetics

Alzheimer's Disease and the Possible Role of Vitamin D

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