Role of Astrocytes in Parkinson’s Disease Associated with Genetic Mutations and Neurotoxicants

Kim, Sang Hoon; Pajarillo, Edward Alain B.; Nyarko-Danquah, Ivan; Aschner, Michael; Lee, Eunsook

doi:10.3390/cells12040622

Cited by 20 publications

(8 citation statements)

References 178 publications

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“…Indeed, HEK-293 cells have been used to ectopically express not only hDAT to study, e.g., the toxic effect of MPTP [ 75 ], but also dopaminergic receptors, e.g., D1 [ 76 ] and/or D5 [ 77 ]. Finally, the choice of a specific cellular model such as HEK-293 cells entails the requirement to focus on one aspect of the disease, e.g., the effect of ROT on LRRK2 WT and KO, while ignoring others (e.g., the effects of astroglia and microglia on neurons exposed to ROT as it occurs in vivo [ 78 ]).…”

Section: Discussionmentioning

confidence: 99%

LRRK2 Knockout Confers Resistance in HEK-293 Cells to Rotenone-Induced Oxidative Stress, Mitochondrial Damage, and Apoptosis

Quintero-Espinosa

Sánchez‐Hernández

Vélez-Pardo

et al. 2023

IJMS

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Leucine-rich repeat kinase 2 (LRRK2) has been linked to dopaminergic neuronal vulnerability to oxidative stress (OS), mitochondrial impairment, and increased cell death in idiopathic and familial Parkinson’s disease (PD). However, how exactly this kinase participates in the OS-mitochondria-apoptosis connection is still unknown. We used clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 LRRK2 knockout (KO) in the human embryonic kidney cell line 293 (HEK-293) to evaluate the cellular response to the mitochondrial inhibitor complex I rotenone (ROT), a well-known OS and cell death inducer. We report successful knockout of the LRRK2 gene in HEK-293 cells using CRISPR editing (ICE, approximately 60%) and flow cytometry (81%) analyses. We found that HEK-293 LRRK2 WT cells exposed to rotenone (ROT, 50 μM) resulted in a significant increase in intracellular reactive oxygen species (ROS, +7400%); oxidized DJ-1-Cys106-SO3 (+52%); phosphorylation of LRRK2 (+70%) and c-JUN (+171%); enhanced expression of tumor protein (TP53, +2000%), p53 upregulated modulator of apoptosis (PUMA, +1950%), and Parkin (PRKN, +22%); activation of caspase 3 (CASP3, +8000%), DNA fragmentation (+35%) and decreased mitochondrial membrane potential (ΔΨm, −58%) and PTEN induced putative kinase 1 (PINK1, −49%) when compared to untreated cells. The translocation of the cytoplasmic fission protein dynamin-related Protein 1 (DRP1) to mitochondria was also observed by colocalization with translocase of the outer membrane 20 (TOM20). Outstandingly, HEK-293 LRRK2 KO cells treated with ROT showed unaltered OS and apoptosis markers. We conclude that loss of LRRK2 causes HEK-293 to be resistant to ROT-induced OS, mitochondrial damage, and apoptosis in vitro. Our data support the hypothesis that LRRK2 acts as a proapoptotic kinase by regulating mitochondrial proteins (e.g., PRKN, PINK1, DRP1, and PUMA), transcription factors (e.g., c-JUN and TP53), and CASP3 in cells under stress conditions. Taken together, these observations suggest that LRRK2 is an important kinase in the pathogenesis of PD.

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Section: Discussionmentioning

confidence: 99%

LRRK2 Knockout Confers Resistance in HEK-293 Cells to Rotenone-Induced Oxidative Stress, Mitochondrial Damage, and Apoptosis

Quintero-Espinosa

Sánchez‐Hernández

Vélez-Pardo

et al. 2023

IJMS

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“…Some details of AD, the most common form of neurodegenerative disease, remain unknown. Amyloid plaques, made of amyloid-beta protein (A), and neurofibrillary tangles, made of hyperphosphorylated tau, are seen extracellularly in AD patients [ 63 , 64 ]. Aβ induces apoptotic cell death in neurons via mechanisms involving oxidative stress, inflammation, and mitochondrial dysfunction, like those characteristics associated with mitochondrial biogenesis deficiencies.…”

Section: Neurodegenerative Disorders and Mitochondrial Dysfunctionmentioning

confidence: 99%

Mitochondria and Brain Disease: A Comprehensive Review of Pathological Mechanisms and Therapeutic Opportunities

Clemente-Suárez,

Redondo-Flórez,

Beltrán-Velasco

et al. 2023

Biomedicines

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Mitochondria play a vital role in maintaining cellular energy homeostasis, regulating apoptosis, and controlling redox signaling. Dysfunction of mitochondria has been implicated in the pathogenesis of various brain diseases, including neurodegenerative disorders, stroke, and psychiatric illnesses. This review paper provides a comprehensive overview of the intricate relationship between mitochondria and brain disease, focusing on the underlying pathological mechanisms and exploring potential therapeutic opportunities. The review covers key topics such as mitochondrial DNA mutations, impaired oxidative phosphorylation, mitochondrial dynamics, calcium dysregulation, and reactive oxygen species generation in the context of brain disease. Additionally, it discusses emerging strategies targeting mitochondrial dysfunction, including mitochondrial protective agents, metabolic modulators, and gene therapy approaches. By critically analysing the existing literature and recent advancements, this review aims to enhance our understanding of the multifaceted role of mitochondria in brain disease and shed light on novel therapeutic interventions.

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“…Thus, given the important role of glial cells in the pathogenesis of PD [ 17 , 18 , 19 , 20 ] and the implicated nAChR regulation of these cells [ 17 , 18 , 21 ], our aim in this review is to provide not only an update on glial nAChRs’ role in glial function but also the potential exploitation of this knowledge in identifying novel targets for this devastating disease.…”

Section: Introductionmentioning

confidence: 99%

Nicotinic Acetylcholine Receptors in Glial Cells as Molecular Target for Parkinson’s Disease

Soares,

Costa,

Ferrolho

et al. 2024

Cells

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Parkinson’s disease (PD) is a progressive neurodegenerative disease characterized by resting tremor, bradykinesia, rigidity, and postural instability that also includes non-motor symptoms such as mood dysregulation. Dopamine (DA) is the primary neurotransmitter involved in this disease, but cholinergic imbalance has also been implicated. Current intervention in PD is focused on replenishing central DA, which provides remarkable temporary symptomatic relief but does not address neuronal loss and the progression of the disease. It has been well established that neuronal nicotinic cholinergic receptors (nAChRs) can regulate DA release and that nicotine itself may have neuroprotective effects. Recent studies identified nAChRs in nonneuronal cell types, including glial cells, where they may regulate inflammatory responses. Given the crucial role of neuroinflammation in dopaminergic degeneration and the involvement of microglia and astrocytes in this response, glial nAChRs may provide a novel therapeutic target in the prevention and/or treatment of PD. In this review, following a brief discussion of PD, we focus on the role of glial cells and, specifically, their nAChRs in PD pathology and/or treatment.

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Role of Astrocytes in Parkinson’s Disease Associated with Genetic Mutations and Neurotoxicants

Cited by 20 publications

References 178 publications

LRRK2 Knockout Confers Resistance in HEK-293 Cells to Rotenone-Induced Oxidative Stress, Mitochondrial Damage, and Apoptosis

LRRK2 Knockout Confers Resistance in HEK-293 Cells to Rotenone-Induced Oxidative Stress, Mitochondrial Damage, and Apoptosis

Mitochondria and Brain Disease: A Comprehensive Review of Pathological Mechanisms and Therapeutic Opportunities

Nicotinic Acetylcholine Receptors in Glial Cells as Molecular Target for Parkinson’s Disease

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