The interplay of aging, genetics and environmental factors in the pathogenesis of Parkinson’s disease

Pang, Shirley Yin-Yu; Ho, Philip Wing-Lok; Liu, Huifang; Leung, Chi-Ting; Li, Lingfei; Chang, Eunice Eun Seo; Ramsden, D.; Ho, Shu‐Leong

doi:10.1186/s40035-019-0165-9

Cited by 261 publications

(210 citation statements)

References 110 publications

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“…Beside α-syn pathology and mitochondrial impairment, numerous other mechanisms have been proposed to contribute to sporadic PD pathogenesis, including neuroinflammation, impaired autophagy, and oxidative stress (Pang et al, 2019). Interestingly, some of these molecular pathways appear to be cross-linked and can be regulated by nuclear factor κB (NF-κB) transcription factors (Kratsovnik et al, 2005;Djavaheri-Mergny et al, 2007;Sarnico et al, 2009a;Morgan and Liu, 2011;Lanzillotta et al, 2015;Kaminska et al, 2016;Nivon et al, 2016;Lingappan, 2018;Nandy et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Nuclear Factor-κB Dysregulation and α-Synuclein Pathology: Critical Interplay in the Pathogenesis of Parkinson’s Disease

Bellucci

Bubacco

Longhena

et al. 2020

Front. Aging Neurosci.

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The loss of dopaminergic neurons of the nigrostriatal system underlies the onset of the typical motor symptoms of Parkinson's disease (PD). Lewy bodies (LB) and Lewy neurites (LN), proteinaceous inclusions mainly composed of insoluble α-synuclein (α-syn) fibrils are key neuropathological hallmarks of the brain of affected patients. Compelling evidence supports that in the early prodromal phases of PD, synaptic terminal and axonal alterations initiate and drive a retrograde degeneration process culminating with the loss of nigral dopaminergic neurons. This notwithstanding, the molecular triggers remain to be fully elucidated. Although it has been shown that α-syn fibrillary aggregation can induce early synaptic and axonal impairment and cause nigrostriatal degeneration, we still ignore how and why α-syn fibrillation begins. Nuclear factor-κB (NF-κB) transcription factors, key regulators of inflammation and apoptosis, are involved in the brain programming of systemic aging as well as in the pathogenesis of several neurodegenerative diseases. The NF-κB family of factors consists of five different subunits (c-Rel, p65/RelA, p50, RelB, and p52), which combine to form transcriptionally active dimers. Different findings point out a role of RelA in PD. Interestingly, the nuclear content of RelA is abnormally increased in nigral dopamine (DA) neurons and glial cells of PD patients. Inhibition of RelA exert neuroprotection against (1-methyl-4-phenyl-1,2,3,6tetrahydropyridine) MPTP and 1-methyl-4-phenylpyridinium (MPP+) toxicity, suggesting that this factor decreases neuronal resilience. Conversely, the c-Rel subunit can exert neuroprotective actions. We recently described that mice deficient for c-Rel develop a PD-like motor and non-motor phenotype characterized by progressive brain α-syn accumulation and early synaptic changes preceding the frank loss of nigrostriatal neurons. This evidence supports that dysregulations in this transcription factors may be involved in the onset of PD. This review highlights observations supporting a possible interplay between NF-κB dysregulation and α-syn pathology in PD, with the aim to disclose novel potential mechanisms involved in the pathogenesis of this disorder.

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Section: Introductionmentioning

confidence: 99%

Nuclear Factor-κB Dysregulation and α-Synuclein Pathology: Critical Interplay in the Pathogenesis of Parkinson’s Disease

Bellucci

Bubacco

Longhena

et al. 2020

Front. Aging Neurosci.

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“…Parkinson's disease (PD) is the second most common neurodegenerative disorder and its main clinicopathological features are loss of dopaminergic neurons (DANs) in the substantia nigra pars compacta (SNpc) and the presence of Lewy bodies 1‐3. In general, the clinical manifestations of PD are divided into motor and nonmotor symptoms, and the latter occur early in disease development and severely affect quality of life 4,5.…”

Section: Introductionmentioning

confidence: 99%

BMAL1 regulation of microglia‐mediated neuroinflammation in MPTP‐induced Parkinson's disease mouse model

et al. 2020

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are contributed equally to this work. AbstractDysfunction of the circadian rhythm is one of most common nonmotor symptoms in Parkinson's disease (PD), but the molecular role of the circadian rhythm in PD is unclear. We here showed that inactivation of brain and muscle ARNT-like 1 (BMAL1) in 1-methyl-4-phenyl-1,2,4,5-tetrahydropyridine (MPTP)-treated mice resulted in obvious motor functional deficit, loss of dopaminergic neurons (DANs) in the substantia nigra pars compacta (SNpc), decrease of dopamine (DA) transmitter, and increased activation of microglia and astrocytes in the striatum. Time on the rotarod or calorie consumption, and food and water intake were reduced in the Bmal1 −/− mice after MPTP treatment, suggesting that absence of Bmal1 may exacerbate circadian and PD motor function. We observed a significant reduction of DANs (~35%) in the SNpc, the tyrosine hydroxylase protein level in the striatum (~60%), the DA (~22%), and 3,4-dihydroxyphenylacetic acid content (~29%), respectively, in MPTP-treated Bmal1 −/− mice. Loss of Bmal1 aggravated the inflammatory reaction both in vivo and in vitro. These findings suggest that BMAL1 may play an essential role in the survival of DANs and maintain normal function of the DA signaling pathway via regulating microglia-mediated neuroinflammation in the brain. K E Y W O R D S circadian rhythm, dopaminergic neurons, neuroinflammation, nonmotor symptoms | 6571 LIU et aL.

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“…Our study identi ed 12 patients with rare variants in the six genes in Chinese ADPD, which makes it more comprehensive and accurate to sum phenotypes for each gene or gene complex. Although late-onset age is usually suggested in autosomal dominantly inherited monogenic PD [29], rare variants were identi ed in our EOPD patients, such as 2 patients carrying CHCHD2 variants, 2 patients carrying TRAP1 variants and 2 patients carrying HSPA9. In accord with previous studies, mutations in the six genes cause PD with varied age of onset, indicating that genetic screening for the six genes in EOPD patients should not be overlooked.…”

Section: Discussionmentioning

confidence: 93%

Systematic analysis of rare variants in mitochondrial function-associated genes for autosomal-dominant Parkinson’s disease in a Chinese population

Chen

et al. 2020

Preprint

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Background Mitochondrial dysfunction is involved in the pathogenicity of Parkinson’s disease (PD). However, the genetic roles of mitochondrial function-associated genes responsible for PD need to be replicated in different cohorts. Methods Whole-exome and Sanger sequencing were used to identify the genetic etiology of 400 autosomal dominant-inherited PD (ADPD) patients. Variants in six dominant inherited mitochondrial function-associated genes, including HTRA2, CHCHD2, CHCHD10, TRAP1, HSPA9 and RHOT1, were analyzed. Results A total of 12 rare variants identified in the five genes accounted for 3% of ADPD cases, including 0.5% in HTRA2, 0.8% in CHCHD2, 1% in TRAP1, 0.3% in RHOT1 and 0.5% in HSPA9. Among them, five novel variants, p.E4A, p.R13Cfs*107 and p.R449X in TRAP1, p.S95N in RHOT1 and p.N180I in HSPA9, were identified in ADPD patients. Evidence of a founder event that occurred exclusively in Asia was identified in two probands with p.P53Afs*37 in CHCHD2, which was further observed in one patient from 300 sporadic cases. Based on burden analysis, CHCHD2 tended to be slightly enriched in ADPD. Clinically, all patients carrying mutations in the genes presented typical motor symptoms and a good response to L-DOPA. Most of them had slower disease progression (8/12) and mild cognitive impairment (9/12), but the age of onset varied. No rare variant was detected in CHCHD10. Conclusion Our study expands the mutation spectra and enhances the understanding of the clinical phenotype of PD patients with mitochondrial function-related gene variants. Additionally, the CHCHD2 gene should be given more attention in PD originating in the Chinese population.

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The interplay of aging, genetics and environmental factors in the pathogenesis of Parkinson’s disease

Cited by 261 publications

References 110 publications

Nuclear Factor-κB Dysregulation and α-Synuclein Pathology: Critical Interplay in the Pathogenesis of Parkinson’s Disease

Nuclear Factor-κB Dysregulation and α-Synuclein Pathology: Critical Interplay in the Pathogenesis of Parkinson’s Disease

BMAL1 regulation of microglia‐mediated neuroinflammation in MPTP‐induced Parkinson's disease mouse model

Systematic analysis of rare variants in mitochondrial function-associated genes for autosomal-dominant Parkinson’s disease in a Chinese population

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