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

Frontiers in Aging Neuroscience, Journal Year: 2022, Volume and Issue: 14

Published: June 20, 2022

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 closely associated with pathogenesis sporadic and familial Because dopaminergic neurons have high energy demand, cells affected by PD exhibit promotes disease-defining loss in substantia nigra pars compacta (SNpc). The mitochondrion has a particularly important role as cellular "powerhouse" neurons. Therefore, mitochondria become promising therapeutic target treatments. This review aims to describe pathology PD, outline genes factors related summarize current knowledge on quality control give an overview strategies targeting neuroprotective interventions

Language: Английский

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Neuropathology of incidental Lewy body & prodromal Parkinson’s disease

Molecular Neurodegeneration, Journal Year: 2023, Volume and Issue: 18(1)

Published: May 12, 2023

Abstract Background Parkinson’s disease (PD) is a progressive neurodegenerative disorder associated with loss of dopaminergic (DA) neurons. Despite symptomatic therapies, there currently no disease-modifying treatment to halt neuronal in PD. A major hurdle for developing and testing such curative therapies results from the fact that most DA neurons are already lost at time clinical diagnosis, rendering them inaccessible therapy. Understanding early pathological changes precede Lewy body pathology (LBP) cell PD will likely support identification novel diagnostic therapeutic strategies help differentiate LBP-dependent -independent alterations. Several previous studies identified specific molecular cellular occur prior appearance bodies (LBs) neurons, but concise map events missing. Methods Here, we conducted literature review identify discuss investigated cases incidental (iLBD), presumed precursor Results Collectively, our demonstrates numerous neuropathological occurring LBs Conclusions Our provides reader summary may targets aid development

Language: Английский

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The Multiple Roles of Autophagy in Neural Function and Diseases

Neuroscience Bulletin, Journal Year: 2023, Volume and Issue: 40(3), P. 363 - 382

Published: Oct. 19, 2023

Abstract Autophagy involves the sequestration and delivery of cytoplasmic materials to lysosomes, where proteins, lipids, organelles are degraded recycled. According way components engulfed, autophagy can be divided into macroautophagy, microautophagy, chaperone-mediated autophagy. Recently, many studies have found that plays an important role in neurological diseases, including Alzheimer's disease, Parkinson's Huntington's neuronal excitotoxicity, cerebral ischemia. maintains cell homeostasis nervous system via degradation misfolded elimination damaged organelles, regulation apoptosis inflammation. AMPK-mTOR, Beclin 1, TP53 , endoplasmic reticulum stress, other signal pathways involved used as potential therapeutic targets for diseases. Here, we discuss role, functions, which will shed light on pathogenic mechanisms diseases suggest novel therapies.

Language: Английский

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Autophagy‐associated non‐coding RNAs: Unraveling their impact on Parkinson's disease pathogenesis

CNS Neuroscience & Therapeutics, Journal Year: 2024, Volume and Issue: 30(5)

Published: May 1, 2024

Parkinson's disease (PD) is a degenerative neurological condition marked by the gradual loss of dopaminergic neurons in substantia nigra pars compacta. The precise etiology PD remains unclear, but emerging evidence suggests significant role for disrupted autophagy-a crucial cellular process maintaining protein and organelle integrity.

Language: Английский

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Autophagy, aging, and age-related neurodegeneration

Neuron, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 1, 2024

Autophagy is a conserved mechanism that degrades damaged or superfluous cellular contents and enables nutrient recycling under starvation conditions. Many neurodegeneration-associated proteins are autophagy substrates, upregulation ameliorates disease in many animal models of neurodegeneration by enhancing the clearance toxic proteins, proinflammatory molecules, dysfunctional organelles. inhibition also induces neuronal glial senescence, phenomenon occurs with increasing age non-diseased brains as well response to stresses. However, aging mutations impair autophagy. This creates potentially detrimental feedback loop whereby accumulation these disease-associated impairs their autophagic clearance, facilitating further aggregation. Thus, understanding how interacts aging, neurodegenerative diseases temporal, cellular, genetic context important for future clinical application autophagy-modulating therapies neurodegeneration.

Language: Английский

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Targeting the Interplay Between Autophagy and the Nrf2 Pathway in Parkinson’s Disease with Potential Therapeutic Implications

Biomolecules, Journal Year: 2025, Volume and Issue: 15(1), P. 149 - 149

Published: Jan. 19, 2025

Parkinson’s disease (PD) is a prevalent neurodegenerative disorder marked by the progressive degeneration of midbrain dopaminergic neurons and resultant locomotor dysfunction. Despite over two centuries recognition as chronic disease, exact pathogenesis PD remains elusive. The onset progression involve multiple complex pathological processes, with dysfunctional autophagy elevated oxidative stress serving critical contributors. Notably, emerging research has underscored interplay between in pathogenesis. Given limited efficacy therapies targeting either dysfunction or stress, it crucial to elucidate intricate mechanisms governing their develop more effective therapeutics. This review overviews role nuclear factor erythroid 2-related 2 (Nrf2), pivotal transcriptional regulator orchestrating cellular defense against these processes. By elucidating key processes PD, this will deepen our comprehensive understanding multifaceted underlying may uncover potential strategies for its prevention treatment.

Language: Английский

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The relationship of alpha-synuclein to mitochondrial dynamics and quality control

Frontiers in Molecular Neuroscience, Journal Year: 2022, Volume and Issue: 15

Published: Aug. 26, 2022

Maintenance of mitochondrial health is essential for neuronal survival and relies upon dynamic changes in the network effective quality control mechanisms including mitochondrial-derived vesicle pathway mitophagy. Mitochondrial dysfunction has been implicated driving pathology several neurodegenerative diseases, Parkinson's disease (PD) where dopaminergic neurons substantia nigra are selectively degenerated. In addition, many genes with PD-associated mutations have defined functions organelle control, indicating that dysregulation may represent a key element pathology. The most well-characterized aspect PD relates to alpha-synuclein; an aggregation-prone protein forms intracellular Lewy-body inclusions. Details how alpha-synuclein exerts its toxicity not completely known, however, dysfunctional mitochondria observed both patients models Accordingly, association between function established. This alpha-synuclein's role transport, dynamics, control. Despite these relationships, there limited research defining direct linking dynamics this review, we will discuss current literature addressing provide insight into proposed promoting functional relationships. We also consider some alternative speculate what relationship might mean physiologically relation PD.

Language: Английский

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Autophagy in Parkinson’s Disease

Biomolecules, Journal Year: 2023, Volume and Issue: 13(10), P. 1435 - 1435

Published: Sept. 22, 2023

Parkinson’s disease (PD) is a devastating associated with accumulation of α-synuclein (α-Syn) within dopaminergic neurons, leading to neuronal death. PD characterized by both motor and non-motor clinical symptoms. Several studies indicate that autophagy, an important intracellular degradation pathway, may be involved in different neurodegenerative diseases including PD. The autophagic process mediates the protein aggregates, damaged unneeded proteins, organelles, allowing their clearance, thereby maintaining cell homeostasis. Impaired autophagy cause abnormal proteins. Incomplete or impaired explain neurotoxic aggregates several Indeed, have suggested contribution α-Syn accumulation, death neuroinflammation. In this review, we summarize recent literature on involvement pathogenesis.

Language: Английский

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Sigma-2 Receptors—From Basic Biology to Therapeutic Target: A Focus on Age-Related Degenerative Diseases

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(7), P. 6251 - 6251

Published: March 26, 2023

There is a large unmet medical need to develop disease-modifying treatment options for individuals with age-related degenerative diseases of the central nervous system. The sigma-2 receptor (S2R), encoded by TMEM97, expressed in brain and retinal cells, regulates cell functions via its co-receptor progesterone membrane component 1 (PGRMC1), through other protein–protein interactions. Studies describing S2R involve manipulation expression or pharmacological modulation using exogenous small-molecule ligands. These studies demonstrate that modulates key pathways involved including autophagy, trafficking, oxidative stress, amyloid-β α-synuclein toxicity. Furthermore, can ameliorate functional deficits cell-based animal models disease. This review summarizes current evidence-based understanding biology function, potential as therapeutic target system, Alzheimer’s disease, α-synucleinopathies, dry macular degeneration.

Language: Английский

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Alpha-Synuclein Contribution to Neuronal and Glial Damage in Parkinson’s Disease

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 25(1), P. 360 - 360

Published: Dec. 26, 2023

Parkinson’s disease (PD) is a complex neurodegenerative characterized by the progressive loss of dopaminergic neurons in substantia nigra and widespread accumulation alpha-synuclein (αSyn) protein aggregates. αSyn aggregation disrupts critical cellular processes, including synaptic function, mitochondrial integrity, proteostasis, which culminate neuronal cell death. Importantly, pathology extends beyond neurons—it also encompasses spreading throughout environment internalization microglia astrocytes. Once internalized, glia can act as neuroprotective scavengers, limit spread αSyn. However, they become reactive, thereby contributing to neuroinflammation progression PD. Recent advances research have enabled molecular diagnosis PD accelerated development targeted therapies. Nevertheless, despite more than two decades research, mechanisms, induction damage remain incompletely understood. Unraveling interplay between αSyn, neurons, may provide insights into initiation progression, bring us closer exploring new effective therapeutic strategies. Herein, we an overview recent studies emphasizing multifaceted nature its impact on both neuron glial damage.

Language: Английский

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