Targeting Mitochondrial Impairment in Parkinson's Disease: Challenges and Opportunities

The underlying pathophysiology of Parkinson's disease is complex, but mitochondrial dysfunction has an established and prominent role. This is supported by an already large and rapidly growing body of evidence showing that the role of mitochondrial (dys)function is central and multifaceted. However, there are clear gaps in knowledge, including the dilemma of explaining why inherited mitochondriopathies do not usually present with parkinsonian symptoms. Many aspects of mitochondrial function are potential therapeutic targets, including reactive oxygen species production, mitophagy, mitochondrial biogenesis, mitochondrial dynamics and trafficking, mitochondrial metal ion homeostasis, sirtuins, and endoplasmic reticulum links with mitochondria. Potential therapeutic strategies may also incorporate exercise, microRNAs, mitochondrial transplantation, stem cell therapies, and photobiomodulation. Despite multiple studies adopting numerous treatment strategies, clinical trials to date have generally failed to show benefit. To overcome this hurdle, more accurate biomarkers of mitochondrial dysfunction are required to detect subtle beneficial effects. Furthermore, selecting study participants early in the disease course, studying them for suitable durations, and stratifying them according to genetic and neuroimaging findings may increase the likelihood of successful clinical trials. Moreover, treatments involving combined approaches will likely better address the complexity of mitochondrial dysfunction in Parkinson's disease. Therefore, selecting the right patients, at the right time, and using targeted combination treatments, may offer the best chance for development of an effective novel therapy targeting mitochondrial dysfunction in Parkinson's disease.

Download Full-text

Genetic Basis and Novel Treatment Strategies in Parkinson's Disease – A Review

10.31531/2581-3080.1000150 ◽

2021 ◽

Vol 5 (1) ◽

pp. 1-5

Author(s):

Nagare Santosh Gangadhar ◽

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Metal Ion ◽

Genetic Basis ◽

Neurodegenerative Disorder ◽

Symptomatic Relief ◽

Ion Homeostasis ◽

Treatment Strategies ◽

Metal Ion Homeostasis ◽

Disease Modifying

Parkinson's disease (PD) is the 2nd most common progressive neurodegenerative disorder after Alzheimer's disease. Approximately 60000 are diagnosed with Parkinson's disease each year and more than 10 million people are living with PD. PD is a neurodegenerative disorder in addition to the causes of PD are so many, it's not caused by a single pathophysiologic disturbance. So many drugs are available to treat PD but all are only for symptomatic relief no one drug is a disease-modifying agent. Although so many targets are available for targeting the Synuclein alpha, mitochondrial oxidative stress, autophagy, targeting glial cell inflammation, targeting metal ion homeostasis. But till now no one drug is successful in targeting these targets. In this review, we have summarized the genetic basis and novel targets available for the disease-modifying strategy for PD.

Download Full-text

Scutellarin inhibits the uninduced and metal-induced aggregation of α-Synuclein and disaggregates preformed fibrils: implications for Parkinson's disease

Biochemical Journal ◽

10.1042/bcj20190705 ◽

2020 ◽

Vol 477 (3) ◽

pp. 645-670 ◽

Cited By ~ 2

Author(s):

Fatima Kamal Zaidi ◽

Shashank Deep

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Metal Ion ◽

Ion Homeostasis ◽

Transition Metal Ions ◽

Alpha Synuclein ◽

Higher Order ◽

Ans Binding ◽

Metal Ion Homeostasis ◽

Induced Aggregation

The aggregation of the protein alpha synuclein (α-Syn), a known contributor in Parkinson's disease (PD) pathogenesis is triggered by transition metal ions through occupational exposure and disrupted metal ion homeostasis. Naturally occurring small molecules such as polyphenols have emerged as promising inhibitors of α-Syn fibrillation and toxicity and could be potential therapeutic agents against PD. Here, using an array of biophysical tools combined with cellular assays, we demonstrate that the novel polyphenolic compound scutellarin efficiently inhibits the uninduced and metal-induced fibrillation of α-Syn by acting at the nucleation stage and stabilizes a partially folded intermediate of α-Syn to form SDS-resistant, higher-order oligomers (∼680 kDa) and also disaggregates preformed fibrils of α-Syn into similar type of higher-order oligomers. ANS binding assay, fluorescence lifetime measurements and cell-toxicity experiments reveal scutellarin-generated oligomers as compact, low hydrophobicity structures with modulated surface properties and significantly reduced cytotoxicity than the fibrillation intermediates of α-Syn control. Fluorescence spectroscopy and isothermal titration calorimetry establish the binding between scutellarin and α-Syn to be non-covalent in nature and of moderate affinity (Ka ∼ 105 M−1). Molecular docking approaches suggest binding of scutellarin to the residues present in the NAC region and C-terminus of monomeric α-Syn and the C-terminal residues of fibrillar α-Syn, demonstrating inhibition of fibrillation upon binding to these residues and possible stabilization of the autoinhibitory conformation of α-Syn. These findings reveal interesting insights into the mechanism of scutellarin action and establish it as an efficient modulator of uninduced as well as metal-induced α-Syn fibrillation and toxicity.

Download Full-text

Mitochondrial Fusion/Fission, Transport and Autophagy in Parkinson's Disease: When Mitochondria Get Nasty

Parkinson s Disease ◽

10.4061/2011/767230 ◽

2011 ◽

Vol 2011 ◽

pp. 1-13 ◽

Cited By ~ 12

Author(s):

Daniela M. Arduíno ◽

A. Raquel Esteves ◽

Sandra M. Cardoso

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mitochondrial Dysfunction ◽

Molecular Basis ◽

Molecular Mechanisms ◽

Mitochondrial Dynamics ◽

Growing Body ◽

Parkinsonian Disorders ◽

Mitochondrial Trafficking

Understanding the molecular basis of Parkinson's disease (PD) has proven to be a major challenge in the field of neurodegenerative diseases. Although several hypotheses have been proposed to explain the molecular mechanisms underlying the pathogenesis of PD, a growing body of evidence has highlighted the role of mitochondrial dysfunction and the disruption of the mechanisms of mitochondrial dynamics in PD and other parkinsonian disorders. In this paper, we comment on the recent advances in how changes in the mitochondrial function and mitochondrial dynamics (fusion/fission, transport, and clearance) contribute to neurodegeneration, specifically focusing on PD. We also evaluate the current controversies in those issues and discuss the role of fusion/fission dynamics in the mitochondrial lifecycle and maintenance. We propose that cellular demise and neurodegeneration in PD are due to the interplay between mitochondrial dysfunction, mitochondrial trafficking disruption, and impaired autophagic clearance.

Download Full-text

Stimulation of electron transport as potential novel therapy in Parkinson's disease with mitochondrial dysfunction

Biochemical Society Transactions ◽

10.1042/bst20140325 ◽

2015 ◽

Vol 43 (2) ◽

pp. 275-279 ◽

Cited By ~ 9

Author(s):

Melissa Vos ◽

Patrik Verstreken ◽

Christine Klein

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Electron Transport ◽

Mitochondrial Dysfunction ◽

Dopaminergic Neurons ◽

Current Therapy ◽

Motor Disorder ◽

Novel Therapy ◽

Transport Chain ◽

Stimulation Of

Parkinson's disease (PD) is a neurodegenerative motor disorder characterized by the loss of dopaminergic neurons. This loss of dopaminergic neurons is the pathological hallmark of the disease that results in the characteristic motor syndrome. Restoration of dopamine levels is the basis of current therapy; however, this does not tackle the cause of the disease. While the aetiology of PD remains mostly elusive, mitochondrial dysfunction has been linked to (at least) part of the PD cases. In this review we discuss recent findings in Drosophila melanogaster showing that stimulation of the electron transport chain is beneficial for PD fly models showing Complex I defects and discuss the possible clinical applications of these findings.

Download Full-text

Nicotinamide riboside alleviates Parkinson’s disease symptoms but downregulates dopamine metabolism upon lactacystin-induced proteostasis failure

10.1101/2021.03.12.435062 ◽

2021 ◽

Author(s):

Giorgio Turconi ◽

Farhan Alam ◽

Tanima SenGupta ◽

Sini Pirnes-Karhu ◽

Soophie Olfat ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Clinical Trials ◽

Mitochondrial Dysfunction ◽

Proteasome Inhibition ◽

Dopamine Metabolism ◽

Nicotinamide Riboside ◽

C Elegans ◽

Unfolded Protein ◽

Age Related

AbstractActivation of mitochondrial metabolism and proteostasis with the NAD+ precursor nicotinamide riboside (NR) has emerged as a potential therapeutic approach for neurodegenerative disorders including Parkinson’s disease (PD). However, despite recently started clinical trials, studies on NR in animal models of PD are scarce. In this study, we investigated the effect of NR in multiple models of PD. In transgenic C. elegans overexpressing α-synuclein, a protein of which aggregation is believed to promote PD, NR rescued PD-like phenotypes including mitochondrial dysfunction and motility defects, decreased oxidative stress, and age-related dopamine (DA) neuron loss. We found that NR eased symptoms of disease by activating the mitochondrial unfolded protein response (UPRmt) via the transcription factor atfs-1. Similarly, in a proteasome inhibitor, lactacystin, -induced mouse model of PD, NR rescued mitochondrial dysfunction and behavioural deficits caused by lactacystin lesion. However, long-term NR supplementation, in conjunction with proteasome inhibition, resulted in decreased DA levels in both the lesioned and unlesioned sides of the substantia nigra with concomitant downregulation of key genes in DA metabolism. Our results suggest specific endpoints that should be monitored in ongoing NR clinical trials.

Download Full-text

The Nrf2/ARE Pathway: A Promising Target to Counteract Mitochondrial Dysfunction in Parkinson's Disease

Parkinson s Disease ◽

10.4061/2011/314082 ◽

2011 ◽

Vol 2011 ◽

pp. 1-14 ◽

Cited By ~ 38

Author(s):

Kemal Ugur Tufekci ◽

Ezgi Civi Bayin ◽

Sermin Genc ◽

Kursad Genc

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mitochondrial Dysfunction ◽

Current Knowledge ◽

Mitochondrial Dynamics ◽

Common Denominator ◽

Related Factor ◽

Neuron Death ◽

Promising Therapeutic Approach ◽

Mitochondrial Functions

Mitochondrial dysfunction is a prominent feature of various neurodegenerative diseases as strict regulation of integrated mitochondrial functions is essential for neuronal signaling, plasticity, and transmitter release. Many lines of evidence suggest that mitochondrial dysfunction plays a central role in the pathogenesis of Parkinson's disease (PD). Several PD-associated genes interface with mitochondrial dynamics regulating the structure and function of the mitochondrial network. Mitochondrial dysfunction can induce neuron death through a plethora of mechanisms. Both mitochondrial dysfunction and neuroinflammation, a common denominator of PD, lead to an increased production of reactive oxygen species, which are detrimental to neurons. The transcription factor nuclear factor E2-related factor 2 (Nrf2, NFE2L2) is an emerging target to counteract mitochondrial dysfunction and its consequences in PD. Nrf2 activates the antioxidant response element (ARE) pathway, including a battery of cytoprotective genes such as antioxidants and anti-inflammatory genes and several transcription factors involved in mitochondrial biogenesis. Here, the current knowledge about the role of mitochondrial dysfunction in PD, Nrf2/ARE stress-response mechanisms, and the evidence for specific links between this pathway and PD are summarized. The neuroprotection of nigral dopaminergic neurons by the activation of Nrf2 through several inducers in PD is also emphasized as a promising therapeutic approach.

Download Full-text

Oxidative Stress, Mitochondrial Dysfunction, and Neuroprotection of Polyphenols with Respect to Resveratrol in Parkinson’s Disease

Biomedicines ◽

10.3390/biomedicines9080918 ◽

2021 ◽

Vol 9 (8) ◽

pp. 918

Author(s):

Heng-Chung Kung ◽

Kai-Jung Lin ◽

Chia-Te Kung ◽

Tsu-Kung Lin

Keyword(s):

Oxidative Stress ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mitochondrial Dysfunction ◽

Mitochondrial Dynamics ◽

Critical Role ◽

Neuronal Loss ◽

Ros Generation ◽

Neuroprotective Effects ◽

Dopaminergic Neuronal Loss

Parkinson’s disease (PD) is the second most common neurodegenerative disease and is characterized by dopaminergic neuronal loss. The exact pathogenesis of PD is complex and not yet completely understood, but research has established the critical role mitochondrial dysfunction plays in the development of PD. As the main producer of cytosolic reactive oxygen species (ROS), mitochondria are particularly susceptible to oxidative stress once an imbalance between ROS generation and the organelle’s antioxidative system occurs. An overabundance of ROS in the mitochondria can lead to mitochondrial dysfunction and further vicious cycles. Once enough damage accumulates, the cell may undergo mitochondria-dependent apoptosis or necrosis, resulting in the neuronal loss of PD. Polyphenols are a group of natural compounds that have been shown to offer protection against various diseases, including PD. Among these, the plant-derived polyphenol, resveratrol, exhibits neuroprotective effects through its antioxidative capabilities and provides mitochondria protection. Resveratrol also modulates crucial genes involved in antioxidative enzymes regulation, mitochondrial dynamics, and cellular survival. Additionally, resveratrol offers neuroprotective effects by upregulating mitophagy through multiple pathways, including SIRT-1 and AMPK/ERK pathways. This compound may provide potential neuroprotective effects, and more clinical research is needed to establish the efficacy of resveratrol in clinical settings.

Download Full-text

αSynuclein and Mitochondrial Dysfunction: A Pathogenic Partnership in Parkinson’s Disease?

Parkinson s Disease ◽

10.1155/2012/829207 ◽

2012 ◽

Vol 2012 ◽

pp. 1-12 ◽

Cited By ~ 5

Author(s):

David Protter ◽

Charmaine Lang ◽

Antony A. Cooper

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mitochondrial Dysfunction ◽

Molecular Mechanisms ◽

Nitrosative Stress ◽

Neurodegenerative Disorder ◽

Mitochondrial Dynamics ◽

Term Therapy ◽

Central Component ◽

Cellular Targets

Parkinson’s Disease (PD) is a complex, chronic, progressive, and debilitating neurodegenerative disorder. Neither a cure nor effective long-term therapy exist and the lack of knowledge of the molecular mechanisms responsible for PD development is a major impediment to therapeutic advances. The protein αSynuclein is a central component in PD pathogenesis yet its cellular targets and mechanism of toxicity remains unknown. Mitochondrial dysfunction is also a common theme in PD patients and this review explores the strong possibility that αSynuclein and mitochondrial dysfunction have an inter-relationship responsible for underlying the disease pathology. Amplifying cycles of mitochondrial dysfunction and αSynuclein toxicity can be envisaged, with either being the disease-initiating factor yet acting together during disease progression. Multiple potential mechanisms exist in which mitochondrial dysfunction and αSynuclein could interact to exacerbate their neurodegenerative properties. Candidates discussed within this review include autophagy, mitophagy, mitochondrial dynamics/fusion/fission, oxidative stress and reactive oxygen species, endoplasmic reticulum stress, calcium, nitrosative stress and αSynuclein Oligomerization.

Download Full-text

Induction of Autophagy by Vasicinone Protects Neural Cells from Mitochondrial Dysfunction and Attenuates Paraquat-Mediated Parkinson’s Disease Associated α-Synuclein Levels

Nutrients ◽

10.3390/nu12061707 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1707 ◽

Cited By ~ 1

Author(s):

Chih-Yang Huang ◽

Kalaiselvi Sivalingam ◽

Marthandam Asokan Shibu ◽

Po-Hsiang Liao ◽

Tsung-Jung Ho ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mitochondrial Dysfunction ◽

Mitochondrial Membrane ◽

Mitochondrial Dynamics ◽

Neural Cells ◽

Oxygen Species ◽

Mitochondrial Reactive Oxygen Species ◽

Neuroprotective Effects ◽

Atg Proteins

Mitochondrial dysfunction and disturbed mitochondrial dynamics were found to be common phenomena in the pathogenesis of Parkinson’s disease (PD). Vasicinone is a quinazoline alkaloid from Adhatoda vasica. Here, we investigated the autophagy/mitophagy-enhancing effect of vasicinone and explored its neuroprotective mechanism in paraquat-mimic PD modal in SH-SY5Y cells. Vasicinone rescued the paraquat-induced loss of cell viability and mitochondrial membrane potential. Subsequently, the accumulation of mitochondrial reactive oxygen species (ROS) was balanced by an increase in the expression of antioxidant enzymes. Furthermore, vasicinone restored paraquat-impaired autophagy and mitophagy regulators DJ-1, PINK-1 and Parkin in SH-SY5Y cells. The vasicinone mediated autophagy pathways were abrogated by treatment with the autophagy inhibitor 3-MA, which lead to increases α-synuclein accumulation and decreased the expression of p-ULK and ATG proteins and the autophagy marker LC3-II compared to that observed without 3-MA treatment. These results demonstrated that vasicinone exerted neuroprotective effects by upregulating autophagy and PINK-1/Parkin mediated mitophagy in SH-SY5Y cells.

Download Full-text