Developmental exposure to the Parkinson’s disease-associated organochlorine pesticide dieldrin alters dopamine neurotransmission in α-synuclein pre-formed fibril (PFF)-injected mice DOI Creative Commons
S. Boyd,

Nathan C. Kuhn,

Joseph R. Patterson

et al.

Toxicological Sciences, Journal Year: 2023, Volume and Issue: 196(1), P. 99 - 111

Published: Aug. 22, 2023

Abstract Parkinson’s disease (PD) is the fastest-growing neurological worldwide, with increases outpacing aging and occurring most rapidly in recently industrialized areas, suggesting a role of environmental factors. Epidemiological, post-mortem, mechanistic studies suggest that persistent organic pollutants, including organochlorine pesticide dieldrin, increase PD risk. In mice, developmental dieldrin exposure causes male-specific exacerbation neuronal susceptibility to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) synucleinopathy. Specifically, α-synuclein (α-syn) pre-formed fibril (PFF) model, leads increased deficits striatal dopamine (DA) turnover motor on challenging beam. Here, we hypothesized alterations DA handling contribute observed changes assessed vesicular monoamine transporter 2 (VMAT2) function release this dieldrin/PFF 2-hit model. Female C57BL/6 mice were exposed 0.3 mg/kg or vehicle every 3 days by feeding, starting at 8 weeks age continuing throughout breeding, gestation, lactation. Male offspring from independent litters underwent unilateral, intrastriatal injections α-syn PFFs 12 age, 3H-DA uptake assays fast-scan cyclic voltammetry performed 4 months post-PFF injection. Dieldrin-induced an slices PFF-injected animals, but no change VMAT2 activity. These results compensatory response synucleinopathy-triggered loss. findings are consistent silent neurotoxicity, where primes nigrostriatal system have exacerbated synucleinopathy absence observable typical markers dysfunction degeneration.

Language: Английский

LRRK2 and idiopathic Parkinson’s disease DOI
Emily M. Rocha, Matthew T. Keeney, Roberto Di Maio

et al.

Trends in Neurosciences, Journal Year: 2022, Volume and Issue: 45(3), P. 224 - 236

Published: Jan. 4, 2022

Language: Английский

Citations

108
Anionic nanoplastic contaminants promote Parkinson’s disease–associated α-synuclein aggregation DOI Creative Commons
Zhiyong Liu, Arpine Sokratian, Addison M. Duda

et al.

Science Advances, Journal Year: 2023, Volume and Issue: 9(46)

Published: Nov. 17, 2023

Recent studies have identified increasing levels of nanoplastic pollution in the environment. Here, we find that anionic contaminants potently precipitate formation and propagation α-synuclein protein fibrils through a high-affinity interaction with amphipathic non-amyloid component (NAC) domains α-synuclein. Nanoplastics can internalize neurons clathrin-dependent endocytosis, causing mild lysosomal impairment slows degradation aggregated In mice, nanoplastics combine to exacerbate spread pathology across interconnected vulnerable brain regions, including strong induction inclusions dopaminergic substantia nigra. These results highlight potential link for further exploration between aggregation associated Parkinson’s disease related dementias.

Language: Английский

Citations

83
Mitochondrial Dysfunction in Parkinson’s Disease: From Mechanistic Insights to Therapy DOI Creative Commons
Xiaoyan Gao, Tuo Yang, Ying Gu

et al.

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

Citations

75
The heterogeneity of Parkinson’s disease DOI Creative Commons
Ullrich Wüllner, Per Borghammer, Chi‐un Choe

et al.

Journal of Neural Transmission, Journal Year: 2023, Volume and Issue: 130(6), P. 827 - 838

Published: May 11, 2023

The heterogeneity of Parkinson's disease (PD), i.e. the various clinical phenotypes, pathological findings, genetic predispositions and probably also implicated pathophysiological pathways pose a major challenge for future research projects therapeutic trail design. We outline several concepts, mechanisms, including presumed roles α-synuclein misfolding aggregation, Lewy bodies, oxidative stress, iron melanin, deficient autophagy processes, insulin incretin signaling, T-cell autoimmunity, gut-brain axis evidence that microbial (viral) agents may induce molecular hallmarks neurodegeneration. hypothesis is discussed, whether PD might indeed be triggered by exogenous (infectious) in susceptible individuals upon entry via olfactory bulb (brain first) or gut (body-first), which would support idea mechanisms change over time. unresolved have contributed to failure past trials, attempted slow course PD. thus conclude patients need personalized approaches tailored specific phenomenological etiologic subtypes disease.

Language: Английский

Citations

67
Disease burden of Parkinson's disease in China and its provinces from 1990 to 2021: findings from the global burden of disease study 2021 DOI Creative Commons

Tingling Xu,

Wenlan Dong,

Jinli Liu

et al.

The Lancet Regional Health - Western Pacific, Journal Year: 2024, Volume and Issue: 46, P. 101078 - 101078

Published: May 1, 2024

Parkinson's disease (PD) has become a public health concern with global ageing. However, comprehensive assessments of the temporal and geographical trend PD burden in China remain insufficient. This study aimed to examine by age, gender, region during 1990-2021.

Language: Английский

Citations

41
Parkinson’s Disease is Predominantly a Genetic Disease DOI Creative Commons
Shen‐Yang Lim, Christine Klein

Journal of Parkinson s Disease, Journal Year: 2024, Volume and Issue: 14(3), P. 467 - 482

Published: March 26, 2024

The discovery of a pathogenic variant in the alpha-synuclein (SNCA) gene Contursi kindred 1997 indisputably confirmed genetic cause subset Parkinson’s disease (PD) patients. Currently, variants one seven established PD genes or strongest known risk factor gene, GBA1, are identified ∼15% patients unselected for age at onset and family history. In this Debate article, we highlight multiple avenues research that suggest an important - some cases even predominant role genetics aetiology, including familial clustering, high rates monogenic selected populations, complete penetrance with certain forms. At first sight, steep increase prevalence exceeding other neurodegenerative diseases may argue against etiology. Notably, principal contribution is conferred by LRRK2 GBA1 and, both cases, characterized overall late age-related penetrance. addition, polygenic plays considerable PD. However, it likely that, majority patients, complex interplay aging, genetic, environmental, epigenetic factors leads to development.

Language: Английский

Citations

25
Epidemiology of Parkinson’s Disease: An Update DOI

Juan R. Deliz,

Caroline M. Tanner, Paulina Gonzàlez‐Latapi

et al.

Current Neurology and Neuroscience Reports, Journal Year: 2024, Volume and Issue: 24(6), P. 163 - 179

Published: April 20, 2024

Language: Английский

Citations

18
Linking environmental risk factors with epigenetic mechanisms in Parkinson’s disease DOI Creative Commons
Maria Tsalenchuk, Steve Gentleman, Sarah J. Marzi

et al.

npj Parkinson s Disease, Journal Year: 2023, Volume and Issue: 9(1)

Published: Aug. 25, 2023

Abstract Sporadic Parkinson’s disease (PD) is a progressive neurodegenerative disease, with complex risk structure thought to be influenced by interactions between genetic variants and environmental exposures, although the full aetiology unknown. Environmental factors, including pesticides, have been reported increase of developing disease. Growing evidence suggests epigenetic changes are key mechanisms which these factors act upon gene regulation, in disease-relevant cell types. We present systematic review critically appraising summarising current body relationship PD inform future research this area. Epigenetic studies relevant animal models yielded promising results, however, humans just emerging. While published currently relatively limited, importance field for elucidation molecular pathogenesis opens clear avenues research. Carefully designed epidemiological carried out patients hold great potential uncover regulatory mechanisms. Therefore, advance burgeoning field, we recommend broadening scope investigations include more increasing sample sizes, focusing on types, recruiting diverse cohorts.

Language: Английский

Citations

35
Different pieces of the same puzzle: a multifaceted perspective on the complex biological basis of Parkinson’s disease DOI Creative Commons
Amica Corda Müller-Nedebock,

Marieke C. J. Dekker,

Matthew J. Farrer

et al.

npj Parkinson s Disease, Journal Year: 2023, Volume and Issue: 9(1)

Published: July 13, 2023

The biological basis of the neurodegenerative movement disorder, Parkinson's disease (PD), is still unclear despite it being 'discovered' over 200 years ago in Western Medicine. Based on current PD knowledge, there are widely varying theories as to its pathobiology. aim this article was explore some these different by summarizing viewpoints laboratory and clinician scientists field, disease. To achieve aim, we posed question thirteen "PD experts" from six continents (for global representation) collated their personal opinions into article. views were varied, ranging toxin exposure a trigger, LRRK2 potential root cause, toxic alpha-synuclein most important etiological contributor. Notably, also growing recognition that definition single should be reconsidered, perhaps each with own unique pathobiology treatment regimen.

Language: Английский

Citations

30
Transient exposure to rotenone causes degeneration and progressive parkinsonian motor deficits, neuroinflammation, and synucleinopathy DOI Creative Commons
Amber D. Van Laar,

Katherine R. Webb,

Matthew T. Keeney

et al.

npj Parkinson s Disease, Journal Year: 2023, Volume and Issue: 9(1)

Published: Aug. 11, 2023

Abstract Individuals with Parkinson’s disease (PD) typically receive a diagnosis once they have developed motor symptoms, at which point there is already significant loss of substantia nigra dopamine neurons, α-synuclein accumulation in surviving and neuroinflammation. Consequently, the clinical presentation may be too late to initiate disease-modifying therapy. In contrast this reality, animal models often involve acute neurodegeneration potential therapies are tested concurrently or shortly after pathogenic insult has begun rather than later when diagnostic symptoms emerge. Therefore, we sought develop model that reflects situation more accurately. Middle-aged rats (7–9 months-old) received single daily intraperitoneal injection rotenone for 5 consecutive days were observed over next 8–9 months. Rotenone-treated showed transient slowing postural instability during exposure but recovered within 9 cessation. Rats remained without behavioral deficits 3–4 months, then progressive abnormalities ensuing As began emerge 3 months exposure, was nigral dopaminergic neurons microglial activation. There delayed frontal cortex, maximal post-rotenone. summary, brief temporally-remote causes neuropathological changes similar disease. This mimics human situation, pathogenesis well-established by time appear. such, provide relevant experimental system test therapeutics.

Language: Английский

Citations

29