LRRK2 and α-Synuclein: Distinct or Synergistic Players in Parkinson’s Disease? DOI Creative Commons
Darren M. O’Hara, Grishma Pawar, Suneil K. Kalia

et al.

Frontiers in Neuroscience, Journal Year: 2020, Volume and Issue: 14

Published: June 17, 2020

Parkinson's disease (PD) is the most common neurodegenerative movement disorder, characterized by prominent degeneration of dopaminergic neurons in substantia nigra and aggregation protein alpha-synuclein within intraneuronal inclusions known as Lewy bodies. Ninety percent PD cases are idiopathic while remaining 10% associated with gene mutations that affect cellular functions ranging from kinase activity to mitochondrial quality control, hinting at a multifactorial process. Mutations LRRK2 SNCA (the coding for alpha-synuclein) cause monogenic forms autosomal dominant PD, polymorphisms either also increased risk PD. Although bodies defining neuropathological feature an appreciable subset patients present clinical phenotype indistinguishable but lack pathology autopsy, suggesting LRRK2-mediated may occur independently aggregation. Here, we examine whether alpha-synuclein, mediators neurodegeneration exist or distinct pathways. Specifically, review evidence preclinical models human studies examining interactions between two proteins. Elucidating degree interplay will be necessary treatment stratification once effective targeted disease-modifying therapies developed.

Language: Английский

The process of Lewy body formation, rather than simply α-synuclein fibrillization, is one of the major drivers of neurodegeneration DOI Creative Commons
Anne‐Laure Mahul‐Mellier, Johannes Burtscher, Niran Maharjan

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2020, Volume and Issue: 117(9), P. 4971 - 4982

Published: Feb. 19, 2020

Parkinson’s disease (PD) is characterized by the accumulation of misfolded and aggregated α-synuclein (α-syn) into intraneuronal inclusions named Lewy bodies (LBs). Although it widely believed that α-syn plays a central role in pathogenesis PD, processes govern fibrillization LB formation remain poorly understood. In this work, we sought to dissect spatiotemporal events involved biogenesis LBs at genetic, molecular, biochemical, structural, cellular levels. Toward goal, further developed seeding-based model generate neuronal reproduces key leading formation, including seeding, fibrillization, recapitulate many organizational features bona fide LBs. Using an integrative omics, biochemical imaging approach, dissected molecular associated with different stages their contribution dysfunction degeneration. addition, demonstrate involves complex interplay between posttranslational modifications, interactions aggregates membranous organelles, mitochondria, autophagosome, endolysosome. Finally, show process rather than simply fibril one major drivers neurodegeneration through disruption functions inducing mitochondria damage deficits, synaptic dysfunctions. We believe represents powerful platform investigate mechanisms clearance screen evaluate therapeutics targeting aggregation formation.

Language: Английский

Citations

538
Mitochondrial Dysfunction and Mitophagy in Parkinson’s Disease: From Mechanism to Therapy DOI

Ana Belén Malpartida,

Matthew G Williamson, Derek P. Narendra

et al.

Trends in Biochemical Sciences, Journal Year: 2020, Volume and Issue: 46(4), P. 329 - 343

Published: Dec. 13, 2020

Language: Английский

Citations

359
Mitophagy pathways in health and disease DOI Creative Commons
Samuel A. Killackey, Dana J. Philpott, Stephen E. Girardin

et al.

The Journal of Cell Biology, Journal Year: 2020, Volume and Issue: 219(11)

Published: Aug. 14, 2020

Mitophagy is an evolutionarily conserved process involving the autophagic targeting and clearance of mitochondria destined for removal. Recent insights into complex nature overlapping pathways regulating mitophagy illustrate mitophagy's essential role in maintaining health mitochondrial network. In this review, we highlight recent studies that have changed way understood, from initiation through lysosomal degradation. We outline numerous mitophagic receptors triggers, with a focus on basal physiologically relevant cues, offering insight why they lead to also explore how maintains homeostasis at organ system levels loss may play diverse group diseases, including cardiovascular, metabolic, neurodegenerative diseases. With disrupted affecting such wide array physiological processes, deeper understanding modulate could provide avenues therapies.

Language: Английский

Citations

188
Causative Links between Protein Aggregation and Oxidative Stress: A Review DOI Open Access

Elise Lévy,

Nadine El Banna, Dorothée Baïlle

et al.

International Journal of Molecular Sciences, Journal Year: 2019, Volume and Issue: 20(16), P. 3896 - 3896

Published: Aug. 9, 2019

Compelling evidence supports a tight link between oxidative stress and protein aggregation processes, which are noticeably involved in the development of proteinopathies, such as Alzheimer's disease, Parkinson's prion disease. The literature is tremendously rich studies that establish functional both revealing can be either causative, or consecutive, to aggregation. Because monitoring highly challenging may often lead artefactual results, cutting-edge technical tools have been developed recently redox field, improving ability measure perturbations biological systems. This review aims at providing an update previously known links aggregation, thereby revisiting long-established relationship processes.

Language: Английский

Citations

166
Alpha-Synuclein Physiology and Pathology: A Perspective on Cellular Structures and Organelles DOI Creative Commons

Luis Daniel Bernal-Conde,

Rodrigo Ramos-Acevedo,

Mario A. Reyes-Hernández

et al.

Frontiers in Neuroscience, Journal Year: 2020, Volume and Issue: 13

Published: Jan. 23, 2020

Alpha-synuclein (α-syn) is localized in cellular organelles of most neurons, but many its physiological functions are only partially understood. α-syn accumulation associated with Parkinson's disease, dementia Lewy bodies and multiple system atrophy as well others synucleinopathies, however, the exact pathomechanisms that underlie these neurodegenerative diseases remain elusive. In this review, we describe what known about function pathophysiological changes different structures organelles, including behavior a prion-like protein. We summarize current knowledge pathological forms, covering effect on each organelle, aggregation toxicity model systems, special interest mitochondria due to relevance during apoptotic process dopaminergic neurons. Moreover, explore exert by interacting chromatin remodeling proteins add or remove histone marks, upregulates own expression resume impairment induce vesicular traffic endoplasmic reticulum. then recapitulate events lead Golgi apparatus fragmentation, caused presence α-syn. Finally, report recent findings α-syn, indirectly produced endolysosomal system. conclusion, important steps into understanding have been made using vivo vitro models, time right start integrating observational studies mechanistic models interactions, order look at more complete picture processes underlying α-synucleinopathies.

Language: Английский

Citations

160
Animal models of Parkinson’s disease: bridging the gap between disease hallmarks and research questions DOI Creative Commons

Axelle Dovonou,

Cyril Bolduc,

Victoria Soto Linan

et al.

Translational Neurodegeneration, Journal Year: 2023, Volume and Issue: 12(1)

Published: July 19, 2023

Abstract Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms. More than 200 years after its first clinical description, PD remains serious affliction that affects growing proportion of the population. Prevailing treatments only alleviate symptoms; there still neither cure targets processes nor therapies modify course disease. Over past decades, several animal models have been developed to study PD. Although no model precisely recapitulates pathology, they provide valuable information contributes our understanding limitations treatment options. This review comprehensively summarizes different available for research, with focus on those induced drugs, neurotoxins, pesticides, genetic alterations, α-synuclein inoculation, viral vector injections. We highlight their characteristics ability reproduce PD-like phenotypes. It essential realize strengths weaknesses each induction technique at disposal are determined research question being asked. Our review, therefore, seeks better aid researchers ensuring concrete discernment classical novel in research.

Language: Английский

Citations

53
Common Mechanisms Underlying α-Synuclein-Induced Mitochondrial Dysfunction in Parkinson’s Disease DOI Open Access

Tahereh Sohrabi,

Behnaz Mirzaei-Behbahani,

Ramin Zadali

et al.

Journal of Molecular Biology, Journal Year: 2023, Volume and Issue: 435(12), P. 167992 - 167992

Published: Feb. 2, 2023

Language: Английский

Citations

44
Key genes and convergent pathogenic mechanisms in Parkinson disease DOI
Robert Coukos, Dimitri Krainc

Nature reviews. Neuroscience, Journal Year: 2024, Volume and Issue: 25(6), P. 393 - 413

Published: April 10, 2024

Language: Английский

Citations

27
The Crucial Role of the Blood–Brain Barrier in Neurodegenerative Diseases: Mechanisms of Disruption and Therapeutic Implications DOI Open Access
Sehwan Kim, Un Ju Jung, Sang Ryong Kim

et al.

Journal of Clinical Medicine, Journal Year: 2025, Volume and Issue: 14(2), P. 386 - 386

Published: Jan. 9, 2025

The blood-brain barrier (BBB) is a crucial structure that maintains brain homeostasis by regulating the entry of molecules and cells from bloodstream into central nervous system (CNS). Neurodegenerative diseases such as Alzheimer's Parkinson's disease, well ischemic stroke, compromise integrity BBB. This leads to increased permeability infiltration harmful substances, thereby accelerating neurodegeneration. In this review, we explore mechanisms underlying BBB disruption, including oxidative stress, neuroinflammation, vascular dysfunction, loss tight junction integrity, in patients with neurodegenerative diseases. We discuss how breakdown contributes neurotoxicity, abnormal accumulation pathological proteins, all which exacerbate neuronal damage facilitate disease progression. Furthermore, potential therapeutic strategies aimed at preserving or restoring function, anti-inflammatory treatments, antioxidant therapies, approaches enhance integrity. Given role neurodegeneration, maintaining its represents promising approach slow prevent progression

Language: Английский

Citations

3
Biological links between traumatic brain injury and Parkinson’s disease DOI Creative Commons
Vedad Delic, Kevin D. Beck, Kevin Pang

et al.

Acta Neuropathologica Communications, Journal Year: 2020, Volume and Issue: 8(1)

Published: April 7, 2020

Abstract Parkinson’s Disease (PD) is a progressive neurodegenerative disorder with no cure. Clinical presentation characterized by postural instability, resting tremors, and gait problems that result from loss of A9 dopaminergic neurons in the substantia nigra pars compacta. Traumatic brain injury (TBI) has been implicated as risk factor for several diseases, but strongest evidence linked to development PD. Mild TBI (mTBI), most common defined minimal, if any, consciousness absence significant observable damage tissue. mTBI responsible 56% higher developing PD U.S. Veterans increases severity injury. While mounting human studies suggests link between PD, fundamental questions whether nucleates pathology or accelerates vulnerable populations remains unanswered. Several promising lines research point inflammation, metabolic dysregulation, protein accumulation potential mechanisms through which can initiate accelerate Amyloid precursor (APP), alpha synuclein (α-syn), hyper-phosphorylated Tau, TAR DNA-binding 43 (TDP-43), are some frequently reported proteins upregulated following also closely Recently, upregulation Leucine Rich Repeat Kinase 2 (LRRK2), found mice TBI. Subset Rab were identified biological substrates LRRK2, extensively late onset Inhibition LRRK2 was be neuroprotective models. The goal this review survey current literature concerning mechanistic overlap particular focus on aforementioned proteins. This will cover application rodent models further our understanding relationship

Language: Английский

Citations

119