scholarly journals A Specific Diplotype H1j/H2 of the MAPT Gene Could Be Responsible for Parkinson’s Disease with Dementia

2020 ◽  
Vol 2020 ◽  
pp. 1-5
Author(s):  
Imane Smaili ◽  
Imane Hajjaj ◽  
Rachid Razine ◽  
Houyam Tibar ◽  
Ayyoub Salmi ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Rare Variants ◽  
Neurodegenerative Disorder ◽  
Age Of Onset ◽  
Copy Number Variations ◽  
Chromosome 17 ◽  
G2019s Mutation ◽  
Mapt Gene ◽  
Genetic And Environmental Factors

Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer disease. Five to ten percent of patients have monogenic form of the disease, while most of sporadic PD cases are caused by the combination of genetic and environmental factors. Microtubule-associated protein tau (MAPT) has been appointed as one of the most important risk factors for several neurodegenerative diseases including PD. MAPT is characterized by an inversion in chromosome 17 resulting in two distinct haplotypes H1 and H2. Studies described a significant association of MAPT H1j subhaplotype with PD risk, while H2 haplotype was associated with Parkinsonism, particularly to its bradykinetic component. We report here an isolated case displaying an akinetic-rigid form of PD, with age of onset of 41 years and a good response to levodopa, who developed dementia gradually during the seven years of disease progression. The patient does not carry the LRRK2 G2019S mutation, copy number variations, nor pathogenic and rare variants in known genes associated with PD. MAPT subhaplotype genotyping revealed that the patient has the H1j/H2 diplotype, his mother H1j/H1j, his two healthy brothers H1j/H1v and his deceased father was by deduction H1v/H2. The H1j/H2 diplotype was shown in a total of 3 PD patients among 80, who also did not have known PD-causing mutation and in 1 out of 92 healthy individual controls. The three patients with this diplotype all have a similar clinical phenotype. Our results suggest that haplotypes H1j and H2 are strong risk factor alleles, and their combination could be responsible for early onset of PD with dementia.

scholarly journals Whole-exome analysis in Parkinson’s disease reveals a high burden of ultra rare variants in early onset cases

2020 ◽  
Author(s):  
Bernabe I. Bustos ◽  
Dimitri Krainc ◽  
Steven J. Lubbe ◽  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Early Onset ◽  
Rare Variants ◽  
Neurodegenerative Disorder ◽  
Age Of Onset ◽  
Late Onset ◽  
Genetic Component ◽  
Genetic Risk Assessment ◽  
Whole Exome

ABSTRACTParkinson’s disease (PD) is a complex neurodegenerative disorder with a strong genetic component. We performed a “hypothesis-free” exome-wide burden-based analysis of different variant frequencies, predicted functional impact and age of onset classes, in order to expand the understanding of rare variants in PD. Analyzing whole-exome data from a total of 1,425 PD cases and 596 controls, we found a significantly increased burden of ultra-rare (URV= private variants absent from gnomAD) protein altering variants (PAV) in early-onset PD cases (EOPD, <40 years old; P=3.95×10−26, beta=0.16, SE=0.02), compared to LOPD cases (>60 years old, late-onset), where more common PAVs (allele frequencies <0.001) showed the highest significance and effect (P=0.026, beta=0.15, SE=0.07). Gene-set burden analysis of URVs in EOPD highlighted significant disease- and tissue-relevant genes, pathways and protein-protein interaction networks that were different to that observed in non-EOPD cases. Heritability estimates revealed that URVs account for 15.9% of the genetic component in EOPD individuals. Our results suggest that URVs play a significant role in EOPD and that distinct etiological bases may exist for EOPD and sporadic PD. By providing new insights into the genetic architecture of PD, our study may inform approaches aimed at novel gene discovery and provide new directions for genetic risk assessment based on disease age of onset.

Parkinson’s Disease

2008 ◽  
Author(s):  
Laura Marsh
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Age Of Onset ◽  
Lewy Bodies ◽  
Biological Marker ◽  
Prevalence Rates ◽  
Parkinsonian Disorders ◽  
Clinical Diagnoses ◽  
Cortical Regions

Parkinson’s disease (PD), the second most common neurodegenerative disorder after Alzheimer’s disease (AD), causes a progressive neurologic syndrome characterized by bradykinesia, tremor, rigidity, and, in its later stages, postural instability. The motor signs of PD correspond to loss of dopaminergic neurons in the substantia nigra pars compacta within the ventral midbrain. Neuronal inclusions, called Lewy bodies, are also present in the same region, but they can also be present in limbic and cortical regions and, along with other neurotransmitter deficits, are associated with nonmotor aspects of the disease. PD is to be distinguished from parkinsonism, a general term that refers to clinical conditions with the same motor phenomena, but without reference to a specific etiology. Prevalence rates of PD vary. Epidemiologic studies show ageadjusted prevalence rates (per 100,000 individuals) range from 104.7 in Japan, 114.6 in the United States, 168.8 in Taiwan, and 258.8 in Sicily (Korell and Tanner, 2005). The disease affects about 1 million individuals in North America—approximately 0.5% to 1% of the population older than age 65 years of age. The average age of onset is about 60 years, but 5% to 10% of patients have young-onset PD, beginning before age 40 (Tanner and Ben-Shlomo, 1999). The disease affects all races, and there is a slightly higher prevalence of PD among men. The diagnosis of PD relies on the clinical history and motor examination, which usually distinguish it from other parkinsonian disorders. However, because there is no biological marker that verifies the diagnosis of PD, neuropathologic findings remain the gold standard for confirmation of the clinical diagnosis. Even at specialized movement disorder centers, autopsy studies reveal that 10% to 20% of patients with clinical diagnoses of PD have other neuropathologic diagnoses (Hughes, Daniel, and Lees, 2001). Two of the three cardinal motor signs (tremor, akinesia/bradykinesia, and rigidity) are required to establish the diagnosis of PD, but these motor features overlap with other parkinsonian disorders. However, in patients without an overt tremor, early signs of PD such as decreased arm swing, limb stiffness, and diminished facial expression can be subtle, and the diagnosis of PD maybe delayed for several years.

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

2020 ◽  
Author(s):  
Yongping Chen ◽  
Xiaojing Gu ◽  
Ruwei Ou ◽  
Lingyu Zhang ◽  
Yanbing Hou ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Function ◽  
Chinese Population ◽  
Autosomal Dominant ◽  
Rare Variants ◽  
Age Of Onset ◽  
Systematic Analysis ◽  
Founder Event ◽  
Mutation Spectra

Abstract 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.

scholarly journals RIC3 variants are not associated with Parkinson's Disease in large European, Latin American, or East Asian cohorts

2021 ◽  
Author(s):  
Kajsa Brolin ◽  
Sara Bandres Ciga ◽  
Hampton Leonard ◽  
Mary B Makarious ◽  
Cornelis Blauwendraat ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Latin American ◽  
Rare Variants ◽  
Neurodegenerative Disorder ◽  
Disease Risk ◽  
East Asian ◽  
European Ancestry ◽  
Common Genetic Variants

Parkinson's disease (PD) is a complex neurodegenerative disorder in which both rare and common genetic variants contribute to disease risk. Multiple genes have been reported to be linked to monogenic PD, but these only explain a fraction of the observed familial aggregation. Rare variants in RIC3 have been suggested to be associated with PD in the Indian population. However, replication studies yielded inconsistent results. We further investigate the role of RIC3 variants in PD in European cohorts using individual-level genotyping data from 14,671 PD patients and 17,667 controls, as well as whole-genome sequencing data from 1,615 patients and 961 controls. We also investigated RIC3 using summary statistics from a Latin American cohort of 1,481 individuals, and from a cohort of 31,575 individuals of East Asian ancestry. We did not identify any association between RIC3 and PD in any of the cohorts. However, more studies of rare variants in non-European ancestry populations, in particular South Asian populations, are necessary to further evaluate the world-wide role of RIC3 in PD etiology.

scholarly journals Curcumin Effectively Rescued Parkinson’s Disease-Like Phenotypes in a Novel Drosophila melanogaster Model with dUCH Knockdown

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Thi Thanh Nguyen ◽  
My Dung Vuu ◽  
Man Anh Huynh ◽  
Masamitsu Yamaguchi ◽  
Linh Thuoc Tran ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Genetic Factors ◽  
Neurodegenerative Disorder ◽  
Appropriate Therapy ◽  
Genetic And Environmental Factors ◽  
The Relationship ◽  
Common Neurodegenerative Disorder

The relationship between oxidative stress and neurodegenerative diseases has been extensively examined, and antioxidants are considered to be a promising approach for decelerating disease progression. Parkinson’s disease (PD) is a common neurodegenerative disorder and affects 1% of the population over 60 years of age. A complex combination of genetic and environmental factors contributes to the pathogenesis of PD. However, since the onset mechanisms of PD have not yet been elucidated in detail, difficulties are associated with developing effective treatments. Curcumin has been reported to have neuroprotective properties in PD models induced by neurotoxins or genetic factors such as α-synuclein, PINK1, DJ-1, and LRRK2. In the present study, we investigated the effects of curcumin in a novel Drosophila model of PD with knockdown of dUCH, a homolog of human UCH-L1. We found that dopaminergic neuron-specific knockdown of dUCH caused impaired movement and the loss of dopaminergic neurons. Furthermore, the knockdown of dUCH induced oxidative stress while curcumin decreased the ROS level induced by this knockdown. In addition, dUCH knockdown flies treated with curcumin had improved locomotive abilities and less severe neurodegeneration. Taken together, with studies on other PD models, these results strongly suggest that treatments with curcumin are an appropriate therapy for PD related to oxidative stress.

scholarly journals Parkinson’s Disease-Related Genes and Lipid Alteration

2021 ◽  
Vol 22 (14) ◽  
pp. 7630
Author(s):  
Milena Fais ◽  
Antonio Dore ◽  
Manuela Galioto ◽  
Grazia Galleri ◽  
Claudia Crosio ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Clinical Manifestations ◽  
Alpha Synuclein ◽  
Experimental Models ◽  
Protein Clearance ◽  
Genetic And Environmental Factors

Parkinson’s disease (PD) is a complex and progressive neurodegenerative disorder with a prevalence of approximately 0.5–1% among those aged 65–70 years. Although most of its clinical manifestations are due to a loss of dopaminergic neurons, the PD etiology is largely unknown. PD is caused by a combination of genetic and environmental factors, and the exact interplay between genes and the environment is still debated. Several biological processes have been implicated in PD, including mitochondrial or lysosomal dysfunctions, alteration in protein clearance, and neuroinflammation, but a common molecular mechanism connecting the different cellular alterations remains incompletely understood. Accumulating evidence underlines a significant role of lipids in the pathological pathways leading to PD. Beside the well-described lipid alteration in idiopathic PD, this review summarizes the several lipid alterations observed in experimental models expressing PD-related genes and suggests a possible scenario in relationship to the molecular mechanisms of neuronal toxicity. PD could be considered a lipid-induced proteinopathy, where alteration in lipid composition or metabolism could induce protein alteration—for instance, alpha-synuclein accumulation—and finally neuronal death.

scholarly journals Parkinson's Disease: Leucine-Rich Repeat Kinase 2 and Autophagy, Intimate Enemies

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
José M. Bravo-San Pedro ◽  
Rubén Gómez-Sánchez ◽  
Elisa Pizarro-Estrella ◽  
Mireia Niso-Santano ◽  
Rosa A. González-Polo ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Clinical Syndrome ◽  
Leucine Rich Repeat ◽  
Disease Etiology ◽  
Clinical Appearance ◽  
A Cell ◽  
Genetic And Environmental Factors

Parkinson's disease is the second common neurodegenerative disorder, after Alzheimer's disease. It is a clinical syndrome characterized by loss of dopamine-generating cells in the substancia nigra, a region of the midbrain. The etiology of Parkinson's disease has long been through to involve both genetic and environmental factors. Mutations in the leucine-rich repeat kinase 2 gene cause late-onset Parkinson's disease with a clinical appearance indistinguishable from Parkinson's disease idiopathic. Autophagy is an intracellular catabolic mechanism whereby a cell recycles or degrades damage proteins and cytoplasmic organelles. This degradative process has been associated with cellular dysfunction in neurodegenerative processes including Parkinson's disease. We discuss the role of leucine-rich repeat kinase 2 in autophagy, and how the deregulations of this degradative mechanism in cells can be implicated in the Parkinson's disease etiology.

scholarly journals Exon Dosage Variations in Brazilian Patients with Parkinson’s Disease: Analysis ofSNCA,PARKIN,PINK1andDJ-1Genes

2012 ◽  
Vol 32 (3) ◽  
pp. 173-178 ◽  
Author(s):  
Karla Cristina Vasconcelos Moura ◽  
Mário Campos Junior ◽  
Ana Lúcia Zuma de Rosso ◽  
Denise Hack Nicaretta ◽  
João Santos Pereira ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Age Of Onset ◽  
Copy Number Variations ◽  
Genetic Studies ◽  
Amplification Method ◽  
Disease Mutations ◽  
Exon 1 ◽  
Sporadic Cases ◽  
Disease Analysis

Parkinson’s disease is one of the most common neurodegenerative disorders associated with aging, reaching ∼ 2% of individuals over 65 years. Knowledge achieved in the last decade about the genetic basis of Parkinson’s disease clearly shows that genetic factors play an important role in the etiology of this disorder. Exon dosage variations account for a high proportion of Parkinson’s disease mutations, mainly forPARKINgene. In the present study, we screened genomic rearrangements inSNCA,PARKIN,PINK1andDJ-1genes in 102 Brazilian Parkinson’s disease patients with early onset (age of onset ≤ 50 years), using the multiplex ligation-dependent probe amplification method. Family history was reported by 24 patients, while 78 were sporadic cases. Screening of exon dosage revealedPARKINandPINK1copy number variations, but no dosage alteration was found inSNCAandDJ-1genes. Most of the carriers harbor heterozygous deletions or duplications in thePARKINgene and only one patient was found to have a deletion inPINK1exon 1. Data about dosage changes are scarce in the Brazilian population, which stresses the importance of including exon dosage analysis in Parkinson’s disease genetic studies.

Rapid Diagnosis of Parkinson’s Disease from Sebum using Paper Spray Ionisation Ion Mobility Mass Spectrometry

2020 ◽  
Author(s):  
Depanjan Sarkar ◽  
Drupad Trivedi ◽  
Eleanor Sinclair ◽  
Sze Hway Lim ◽  
Caitlin Walton-Doyle ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Ion Mobility ◽  
Neurodegenerative Disorder ◽  
Treatment Options ◽  
Ion Mobility Mass Spectrometry ◽  
Paper Spray ◽  
Molecular Features ◽  
Validation Set

Parkinson’s disease (PD) is the second most common neurodegenerative disorder for which identification of robust biomarkers to complement clinical PD diagnosis would accelerate treatment options and help to stratify disease progression. Here we demonstrate the use of paper spray ionisation coupled with ion mobility mass spectrometry (PSI IM-MS) to determine diagnostic molecular features of PD in sebum. PSI IM-MS was performed directly from skin swabs, collected from 34 people with PD and 30 matched control subjects as a training set and a further 91 samples from 5 different collection sites as a validation set. PSI IM-MS elucidates ~ 4200 features from each individual and we report two classes of lipids (namely phosphatidylcholine and cardiolipin) that differ significantly in the sebum of people with PD. Putative metabolite annotations are obtained using tandem mass spectrometry experiments combined with accurate mass measurements. Sample preparation and PSI IM-MS analysis and diagnosis can be performed ~5 minutes per sample offering a new route to for rapid and inexpensive confirmatory diagnosis of this disease.

Visual Effects of Deep Brain Stimulation in a Patient with Parkinson’s Disease

2019 ◽  
pp. 158-173
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Deep Brain Stimulation ◽  
Visual System ◽  
Brain Stimulation ◽  
Neurodegenerative Disorder ◽  
Initial Examination ◽  
Before And After ◽  
Deep Brain ◽  
Cover Test

Background: Parkinson’s disease (PD) is a progressive neurodegenerative disorder caused by a dopamine deficiency that presents with motor symptoms. Visual disorders can occur concomitantly but are frequently overlooked. Deep brain stimulation (DBS) has been an effective treatment to improve tremors, stiffness and overall mobility, but little is known about its effects on the visual system. Case Report: A 75-year-old Caucasian male with PD presented with longstanding binocular diplopia. On baseline examination, the best-corrected visual acuity was 20/25 in each eye. On observation, he had noticeable tremors with an unsteady gait. Distance alternating cover test showed exophoria with a right hyperphoria. Near alternating cover test revealed a significantly larger exophoria accompanied by a reduced near point of convergence. Additional testing with a 24-2 Humphrey visual field and optical coherence tomography (OCT) of the nerve and macula were unremarkable. The patient underwent DBS implantation five weeks after initial examination, and the device was activated four weeks thereafter. At follow up, the patient still complained of intermittent diplopia. There was no significant change in the manifest refraction or prism correction. On observation, the patient had remarkably improved tremors with a steady gait. All parameters measured were unchanged. The patient was evaluated again seven months after device activation. Although vergence ranges at all distances were improved, the patient was still symptomatic for intermittent diplopia. OCT scans of the optic nerve showed borderline but symmetric thinning in each eye. All other parameters measured were unchanged. Conclusion: The case found no significant changes on ophthalmic examination after DBS implantation and activation in a patient with PD. To the best of the authors’ knowledge, there are no other cases in the literature that investigated the effects of DBS on the visual system pathway in a patient with PD before and after DBS implantation and activation.

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