Early-Onset Parkinson Disease Screening in Patients From Nigeria

Introduction: Nigeria is one of the most populated countries in the world; however, there is a scarcity of studies in patients with age-related neurodegenerative diseases, such as Parkinson disease (PD). The aim of this study was to screen patients with PD including a small cohort of early-onset PD (EOPD) cases from Nigeria for PRKN, PINK1, DJ1, SNCA multiplication, and LRRK2 p.G2019S.Methods: We assembled a cohort of 109 Nigerian patients with PD from the four main Nigerian tribes: Yoruba, Igbo, Edo, and Hausa. Fifteen cases [14 from the Yoruba tribe (93.3%)] had EOPD (defined as age-at-onset <50 years). All patients with EOPD were sequenced for the coding regions of PRKN, PINK1, and DJ1. Exon dosage analysis was performed with a multiplex ligation-dependent probe amplification assay, which also included a SNCA probe and LRRK2 p.G2019S. We screened for LRRK2 p.G2019S in the entire PD cohort using a genotyping assay. The PINK1 p.R501Q functional analysis was conducted.Results: In 15 patients with EOPD, 22 variants were observed [PRKN, 9 (40.9%); PINK1, 10 (45.5%); and DJ1, 3 (13.6%)]. Three (13.6%) rare, nonsynonymous variants were identified, but no homozygous or compound heterozygous carriers were found. No exonic rearrangements were present in the three genes, and no carriers of SNCA genomic multiplications or LRRK2 p.G2019S were identified. The PINK1 p.R501Q functional analysis revealed pathogenic loss of function.Conclusion: More studies on age-related neurodegenerative diseases are needed in sub-Saharan African countries, including Nigeria. Population-specific variation may provide insight into the genes involved in PD in the local population but may also contribute to larger studiesperformed in White and Asian populations.

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Novel Biallelic NSUN3 Variants Cause Early-Onset Mitochondrial Encephalomyopathy and Seizures

Journal of Molecular Neuroscience ◽

10.1007/s12031-020-01595-8 ◽

2020 ◽

Vol 70 (12) ◽

pp. 1962-1965

Author(s):

Arumugam Paramasivam ◽

Angamuthu K. Meena ◽

Challa Venkatapathi ◽

Robert D.S. Pitceathly ◽

Kumarasamy Thangaraj

Keyword(s):

Gene Expression ◽

Functional Analysis ◽

Mitochondrial Disease ◽

Early Onset ◽

Mitochondrial Encephalomyopathy ◽

The Novel ◽

Loss Of Function ◽

Chemical Modifications ◽

Phenotypic Spectrum ◽

Pathogenic Effects

Abstract Epitranscriptomic systems enable post-transcriptional modifications of cellular RNA that are essential for regulating gene expression. Of the ~ 170 known RNA chemical modifications, methylation is among the most common. Loss of function mutations in NSUN3, encoding the 5-methylcytosine (m5C) methyltransferase NSun3, have been linked to multisystem mitochondrial disease associated with combined oxidative phosphorylation deficiency. Here, we report a patient with early-onset mitochondrial encephalomyopathy and seizures in whom the novel biallelic NSUN3 missense variants c.421G>C (p.A141P) and c.454T>A (p.C152S) were detected. Segregation studies and in silico functional analysis confirmed the likely pathogenic effects of both variants. These findings expand the molecular and phenotypic spectrum of NSUN3-related mitochondrial disease.

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Genetic Evidence Linking Age-Dependent Attenuation of the 26S Proteasome with the Aging Process

Molecular and Cellular Biology ◽

10.1128/mcb.01227-08 ◽

2008 ◽

Vol 29 (4) ◽

pp. 1095-1106 ◽

Cited By ~ 164

Author(s):

Ayako Tonoki ◽

Erina Kuranaga ◽

Takeyasu Tomioka ◽

Jun Hamazaki ◽

Shigeo Murata ◽

...

Keyword(s):

Neurodegenerative Diseases ◽

Life Span ◽

Cellular Protein ◽

Proteasome Activity ◽

26S Proteasome ◽

Loss Of Function ◽

Ubiquitinated Proteins ◽

Age Related ◽

Age Dependent ◽

Progressive Neurodegeneration

ABSTRACT The intracellular accumulation of unfolded or misfolded proteins is believed to contribute to aging and age-related neurodegenerative diseases. However, the links between age-dependent proteotoxicity and cellular protein degradation systems remain poorly understood. Here, we show that 26S proteasome activity and abundance attenuate with age, which is associated with the impaired assembly of the 26S proteasome with the 19S regulatory particle (RP) and the 20S proteasome. In a genetic gain-of-function screen, we characterized Rpn11, which encodes a subunit of the 19S RP, as a suppressor of expanded polyglutamine-induced progressive neurodegeneration. Rpn11 overexpression suppressed the age-related reduction of the 26S proteasome activity, resulting in the extension of flies' life spans with suppression of the age-dependent accumulation of ubiquitinated proteins. On the other hand, the loss of function of Rpn11 caused an early onset of reduced 26S proteasome activity and a premature age-dependent accumulation of ubiquitinated proteins. It also caused a shorter life span and an enhanced neurodegenerative phenotype. Our results suggest that maintaining the 26S proteasome with age could extend the life span and suppress the age-related progression of neurodegenerative diseases.

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Application of survival analysis to the inception of dementia

Psychological Medicine ◽

10.1017/s0033291700010345 ◽

1986 ◽

Vol 16 (3) ◽

pp. 583-593 ◽

Cited By ~ 9

Author(s):

Elizabeth Sturt

Keyword(s):

Survival Analysis ◽

Individual Differences ◽

Statistical Methods ◽

Early Onset ◽

Age At Onset ◽

Analytical Techniques ◽

Early Onset Dementia ◽

Degenerative Process ◽

Age Related ◽

The Difference

SynopsisThe age at onset of dementia of the Alzheimer, Pick or senile type in relatives of probands with early onset dementia was examined using survival analytical techniques applied to data collected by Sjögren et al. (1952). Female relatives were found to have a higher risk of dementia than males, and there was a deficit of affected brothers compared with fathers of probands. In these comparisons due allowance was made for age at the last observation of each relative. Relatives of probable and definite Pick probands had a higher risk than relatives of probable and definite Alzheimer probands, but the difference was not significant and dementia did not occur at an earlier age to the former group.For the relatives as a whole, and for subgroups of relatives, the risk of dementia increased with age, at least up to age 80. It is hypothesized that the pattern of the age-related hazard of dementia is due to the nature of the dementing process; that this slow degenerative process is widespread; and that individual differences in the rate of the process are under the influence of genes. The statistical methods are explained in detail as they have rarely been applied to dementia before, though Chase et al. (1983) have used life tables and survival analysis in testing genetic hypotheses, with an application to Alzheimer's disease.

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Evaluation of Peripheral Immune Activation in Amyotrophic Lateral Sclerosis

10.21203/rs.3.rs-31982/v1 ◽

2020 ◽

Author(s):

Mengli Wang ◽

Zhen Liu ◽

Juan Du ◽

Yanchun Yuan ◽

Bin Jiao ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Neurodegenerative Diseases ◽

Early Onset ◽

Late Onset ◽

Meta Analysis ◽

Age At Onset ◽

Serum Levels ◽

Patient Groups ◽

Als Patients ◽

Lateral Sclerosis

Abstract Background: Accumulating evidence has revealed that immunity plays an important role in amyotrophic lateral sclerosis (ALS) progression. However, the results regarding the serum levels of immunoglobulin and complement are inconsistent in patients with ALS. Although immune dysfunctions have also been reported in patients with other neurodegenerative diseases, few studies have explored whether immune dysfunction in ALS is similar to that in other neurodegenerative diseases.Methods: Serum levels of immunoglobulin and complement were measured in 245 patients with ALS, 65 patients with multiple system atrophy (MSA), 60 patients with Parkinson’s disease (PD), and 82 healthy controls (HCs). A meta-analysis including data from this study was performed to evaluate the differences in the levels of immunoglobulin and complement between ALS patients and HCs. The serum levels of immunoglobulin and complement were compared between patient groups and HCs or between ALS patient groups established by age at onset, site at onset, disease duration, or disease severity. The correlations between the levels of immunoglobulin and complement and the clinical characteristics of ALS were analysed using Spearman correlation analysis.Results: The pooled results showed that patients with ALS had higher C4 levels than did HCs, and no significant differences between these two groups in IgG, IgA, IgM, or C3 levels were found. Multiple comparisons revealed that there were no significant differences between patients with ALS and other neurodegenerative diseases in IgG, IgA, IgM, C3, or C4 levels. In addition, the IgG levels were lower in early-onset ALS patients than in late-onset ALS patients and HCs. The correlations between age at onset of ALS and IgG and IgA levels were significantly positive. Moreover, spinal-onset ALS patients had lower serum IgG levels than did HCs, but no difference was found between bulbar-onset ALS patients and HCs.Conclusions: Peripheral immunity abnormalities existed in patients with ALS, and lower IgG levels were associated with early-onset ALS.

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Compound heterozygous mutations in PARK2 causing early-onset Parkinson disease

Medicine ◽

10.1097/md.0000000000014228 ◽

2019 ◽

Vol 98 (5) ◽

pp. e14228 ◽

Cited By ~ 4

Author(s):

Yu-Qing Fang ◽

Fei Mao ◽

Mei-Jia Zhu ◽

Xiu-Hua Li

Keyword(s):

Parkinson Disease ◽

Early Onset ◽

Compound Heterozygous ◽

Compound Heterozygous Mutations

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Trigonelline Extends the Lifespan of C. Elegans and Delays the Progression of Age-Related Diseases by Activating AMPK, DAF-16, and HSF-1

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/7656834 ◽

2021 ◽

Vol 2021 ◽

pp. 1-11

Author(s):

Wen-Yu Zeng ◽

Lin Tan ◽

Cong Han ◽

Zhuo-Ya Zheng ◽

Gui-Sheng Wu ◽

...

Keyword(s):

Caenorhabditis Elegans ◽

Neurodegenerative Diseases ◽

Stress Resistance ◽

Aging Effect ◽

Loss Of Function ◽

Asian Countries ◽

C Elegans ◽

Age Related ◽

Anti Oxidant ◽

Pathogenic Effects

Trigonelline is the main alkaloid with bioactivity presented in fenugreek, which was used in traditional medicine in Asian countries for centuries. It is reported that trigonelline has anti-inflammatory, anti-oxidant, and anti-pathogenic effects. We are wondering whether trigonelline have anti-aging effect. We found that 50 μM of trigonelline had the best anti-aging activity and could prolong the lifespan of Caenorhabditis elegans (C. elegans) by about 17.9%. Trigonelline can enhance the oxidative, heat, and pathogenic stress resistance of C. elegans. Trigonelline could also delay the development of neurodegenerative diseases, such as AD, PD, and HD, in models of C. elegans. Trigonelline could not prolong the lifespan of long-lived worms with loss-of-function mutations in genes regulating energy and nutrition, such as clk-1, isp-1, eat-2, and rsks-1. Trigonelline requires daf-16, hsf-1, and aak-2 to extend the lifespan of C. elegans. Trigonelline can also up-regulate the expression of daf-16 and hsf-1 targeted downstream genes, such as sod-3, gst-4, hsp-16.1, and hsp-12.6. Our results can be the basis for developing trigonelline-rich products with health benefits, as well as for further research on the pharmacological usage of trigonelline.

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When It Comes to an End: Oxidative Stress Crosstalk with Protein Aggregation and Neuroinflammation Induce Neurodegeneration

Antioxidants ◽

10.3390/antiox9080740 ◽

2020 ◽

Vol 9 (8) ◽

pp. 740 ◽

Cited By ~ 3

Author(s):

Patrycja Michalska ◽

Rafael León

Keyword(s):

Oxidative Stress ◽

Neurodegenerative Diseases ◽

Energy Demand ◽

Molecular Mechanisms ◽

Neuronal Damage ◽

High Energy ◽

Antioxidant Defenses ◽

Loss Of Function ◽

Age Related ◽

The Brain

Neurodegenerative diseases are characterized by a progressive loss of neurons in the brain or spinal cord that leads to a loss of function of the affected areas. The lack of effective treatments and the ever-increasing life expectancy is raising the number of individuals affected, having a tremendous social and economic impact. The brain is particularly vulnerable to oxidative damage given the high energy demand, low levels of antioxidant defenses, and high levels of metal ions. Driven by age-related changes, neurodegeneration is characterized by increased oxidative stress leading to irreversible neuronal damage, followed by cell death. Nevertheless, neurodegenerative diseases are known as complex pathologies where several mechanisms drive neuronal death. Herein we discuss the interplay among oxidative stress, proteinopathy, and neuroinflammation at the early stages of neurodegenerative diseases. Finally, we discuss the use of the Nrf2-ARE pathway as a potential therapeutic strategy based on these molecular mechanisms to develop transformative medicines.

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Phase analysis identifies compound heterozygous deletions of the PARK2 gene in patients with early-onset Parkinson disease

Clinical Genetics ◽

10.1111/j.1399-0004.2011.01693.x ◽

2011 ◽

Vol 82 (1) ◽

pp. 77-82 ◽

Cited By ~ 22

Author(s):

S Y Kim ◽

M W Seong ◽

B S Jeon ◽

S Y Kim ◽

H S Ko ◽

...

Keyword(s):

Parkinson Disease ◽

Phase Analysis ◽

Early Onset ◽

Compound Heterozygous

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Loss-of-function mutations inRAB39Bare associated with typical early-onset Parkinson disease

Neurology Genetics ◽

10.1212/nxg.0000000000000009 ◽

2015 ◽

Vol 1 (1) ◽

pp. e9 ◽

Cited By ~ 51

Author(s):

Suzanne Lesage ◽

Jose Bras ◽

Florence Cormier-Dequaire ◽

Christel Condroyer ◽

Aude Nicolas ◽

...

Keyword(s):

Parkinson Disease ◽

Early Onset ◽

Loss Of Function

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Evaluation of Peripheral Immune Activation in Amyotrophic Lateral Sclerosis

10.21203/rs.3.rs-59383/v1 ◽

2020 ◽

Author(s):

Mengli Wang ◽

Zhen Liu ◽

Juan Du ◽

Yanchun Yuan ◽

Bin Jiao ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Neurodegenerative Diseases ◽

Early Onset ◽

Late Onset ◽

Meta Analysis ◽

Age At Onset ◽

Serum Levels ◽

Als Patients ◽

Immune Dysfunctions ◽

Lateral Sclerosis

Abstract Background: Accumulating evidence has revealed that immunity plays an important role in amyotrophic lateral sclerosis (ALS) progression. However, the results regarding the serum levels of immunoglobulin and complement are inconsistent in patients with ALS. Although immune dysfunctions have also been reported in patients with other neurodegenerative diseases, few studies have explored whether immune dysfunction in ALS is similar to that in other neurodegenerative diseases.Methods: Serum levels of immunoglobulin and complement were measured in 245 patients with ALS, 65 patients with multiple system atrophy (MSA), 60 patients with Parkinson’s disease (PD), and 82 healthy controls (HCs). The serum levels of immunoglobulin and complement were compared among different groups, and the differences in the levels of immunoglobulin and complement between ALS patients and HCs were evaluated using meta-analysis including data from this study. In addition, the association between vitamins and clinical ALS characteristics were evaluated.Results: Patients with ALS had higher C4 levels than did HCs. No significant differences existed between patients with ALS and other neurodegenerative diseases in IgG, IgA, IgM, C3, or C4 levels. The IgA levels were lower in early-onset ALS patients than in late-onset ALS patients. The correlations between age at onset of ALS and IgG or IgA levels were significantly positive.Conclusions: Peripheral immunity abnormalities existed in patients with ALS, and lower IgA levels were associated with early-onset ALS.

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