scholarly journals Zinc supplement greatly improves the condition of parkin mutant Drosophila

2010 ◽  
Vol 391 (5) ◽  
pp. 513-518 ◽  
Author(s):  
Nidhi Saini ◽  
Walter Schaffner
Keyword(s):  
Zinc Supplementation ◽  
Neurodegenerative Disorder ◽  
Disease Model ◽  
Causative Factor ◽  
Gene Encoding ◽  
Zinc Supplement ◽  
Redox Active ◽  
Familial Form ◽  
Extended Lifespan ◽  
Zinc Concentrations

Abstract Parkinson's disease (PD) is a progressive neurodegenerative disorder in which oxidative stress is implicated as a major causative factor. Mutations in the gene encoding Parkin, a ubiquitin ligase, are responsible for a familial form of PD. In a Drosophila disease model lacking Parkin (park25 null mutant), we tested the effect of zinc supplementation. Zinc is an essential trace metal and a component of many enzymes and transcriptional regulators. Unlike copper and iron, zinc is not redox-active and under most conditions serves as an antioxidant. We find that the condition of parkin mutants raised on zinc-supplemented food is greatly improved. At zinc concentrations where controls begin to show adverse effects as a result of the metal supplement, parkin mutants perform best, as manifested in a higher frequency of reaching adulthood, extended lifespan and improved motoric abilities.

scholarly journals Murine models of Parkinson’s disease caused by an increased concentration of α‑synuclein

2019 ◽  
Vol 73 ◽  
pp. 38-46
Author(s):  
Adriana Wawer ◽  
Ilona Joniec-Maciejak ◽  
Anna Sznejder-Pachołek ◽  
Dagmara Mirowska-Guzel
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Viral Vectors ◽  
Disease Model ◽  
Lewy Bodies ◽  
Dopamine Metabolism ◽  
Pathological Process ◽  
Gene Encoding ◽  
Familial Form ◽  
Activity Of Enzymes

Parkinson’s disease (PD) is a chronic, progressive neurodegenerative disease of central nervous system. Despite many years of research its pathogenesis remains elusive. The main pathological process observed in PD is the degeneration of dopaminergic neurons in the substantia nigra and the reduction in the concentration of dopamine and its metabolites in the striatum and basal ganglia. In addition, a reduction in the activity of enzymes involved in the synthesis and metabolism of dopamine (e.g. tyrosine hydroxylase) is observed. The process of neurodegeneration is accompanied by the development of inflammatory reaction and the formation of intraneuronal inclusions - Lewy’s bodies, which containing mainly of α‑synuclein (ASN). The presence of ASN in Lewy bodies and the association of mutations in the gene encoding ASN with the familial form of the disease indicates the important role of this protein in the pathogenesis of PD. ASN is a small protein widely distributed in the brain. Under physiological conditions it is involved, among others, in dopamine metabolism. Changes in ASN levels due to its aggregation, overexpression or decreased expression may disrupt dopaminergic system functions and contribute to the neurodegeneration process observed in PD. Our paper is focused on murine ASN-based models of PD. In this review we describe models based on transgenic mice, viral vectors containing the ASN gene, and those in which elevated ASN levels are obtained by intracerebral protein administration. We briefly discuss the advantages of developed models and their numerous limitations We also highlight the need for further search for the ideal disease model.

scholarly journals Adult hippocampal neurogeneris and amyloid-ß: reproducibility of a sporadic Alzheimer's disease model

2020 ◽  
Author(s):  
Sara Paulo ◽  
Leonor Ribeiro-Rodrigues ◽  
Rui S Rodrigues ◽  
Joana M Mateus ◽  
João Fonseca-Gomes ◽  
...  
Keyword(s):  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Memory Performance ◽  
Treatment Options ◽  
Disease Model ◽  
Dendritic Morphology ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Familial Form ◽  
Male Wistar Rats

Late-onset sporadic Alzheimers disease (AD) is the most common neurodegenerative disorder worldwide, yet present treatment options are still very limited. Modulating adult hippocampal neurogenesis (AHN) as a potential therapeutic target for AD has been explored. However, how the process is regulated in AD remains unclear, as studies show controversial results, arising mainly from models of the familial form. Hence, in the present work, aiming at characterizing AHN in a model of the initial stages of sporadic AD, male Wistar rats were intracerebroventricularly injected with an Aβ1-42 peptide solution. Behaviour tests carried out two weeks after the injection unexpectedly revealed no impact on locomotor activity (open field), anxious-related behaviour (elevated plus maze) or learning and memory performance (novel object recognition, Y-maze, Morris water maze). Assessment of neurogenic markers one month after 5-bromo-2-deoxyuridine administration showed abnormally enhanced dendritic morphology of immature neurons in the dentate gyrus, while proliferation and neuronal differentiation were preserved. As brain-derived neurotrophic factor signalling has been shown to be compromised in the presence of Aβ due to the cleavage of TrkB full-length receptors, the levels of these receptors isoforms were evaluated. No evidence of cleavage was found at 3 or 14 days post-Aβ-infusion. Consistently, the levels of Aβ1-42 species were unaltered at these timepoints, as was the number of astrocytes and microglia. Overall, although this model has been previously described as a model of sporadic AD, the expected behavioural, cellular or molecular phenotypes were not observed, further highlighting the variability of results found in the literature.

scholarly journals Family with atypical Parkinsonism due to CHCHD10 gene mutation

2021 ◽  
Author(s):  
Emília Correia Souto ◽  
Carolina Maria Marin ◽  
Gustavo Carvalho Costa ◽  
Igor Braga Farias ◽  
Bruno de Mattos Lombardi Badia ◽  
...  
Keyword(s):  
Neurodegenerative Disorder ◽  
Wide Spectrum ◽  
Poor Performance ◽  
Thigh Muscle ◽  
Motor Symptoms ◽  
Atypical Parkinsonism ◽  
Mitochondrial Mutation ◽  
Brazilian Woman ◽  
Dementia Syndrome ◽  
Familial Form

Introduction: Parkinson’s disease - PD is the second most common agerelated neurodegenerative disorder. Characterized by a variety of motor and non-motor symptoms that relate to the loss of dopaminergic neurons in the midbrain black substance. Although most cases of PD are sporadic, 5–10% of patients have monogenetic mutations with a description of more than 20 genes for the familial form. Mitochondrial mutation in CHCHD10 has also been reported to be associated with a wide spectrum of neurodegenerative disorders, including PD. Objectives: Description of a rare recently described genetic cause of autosomal dominant parkinsonism. Methodology: Describe the case of a Brazilian woman with atypical parkinsonism due to CHCHD10 pathogenic variant that was followed up in our service. Result: Female, 64 years old. “. He started episodes of imbalance about 5 years ago, with falls, in addition to limb stiffness, worse on the left. 4 years ago, he started myalgia to great efforts with low subsequent tolerance to light effort. 1 year ago with urinary incontinence and choking past of poor performance in physical activities without pre-motor symptoms FAMILY: mother with clinical picture of possible dementia syndrome at age 60, history in the maternal family of myalgia, intolerance to physical exercise and hearing loss in adulthood. EXOMA: presence of variant c.146C > T (p.Ala49Val) in simple heterozygosity without CHCHD10 gene. MRI with thigh muscle hypotrophy in anterior and posterior thigh compartments; slight muscle edema in the legs. Conclusion: Pathogenic variants in the CHCHD10 gene should be considered in cases of atypical parkinsonism, especially in cases of positive familial history of mitochondrial myopathy or dementia.

scholarly journals FACS-array–based cell purification yields a specific transcriptome of striatal medium spiny neurons in a murine Huntington disease model

2020 ◽  
Vol 295 (29) ◽  
pp. 9768-9785 ◽  
Author(s):  
Haruko Miyazaki ◽  
Tomoyuki Yamanaka ◽  
Fumitaka Oyama ◽  
Yoshihiro Kino ◽  
Masaru Kurosawa ◽  
...  
Keyword(s):  
Gene Expression ◽  
Huntington Disease ◽  
Fluorescent Protein ◽  
Neurodegenerative Disorder ◽  
Disease Model ◽  
Medium Spiny Neuron ◽  
Cag Repeats ◽  
Specific Gene ◽  
Protein Marker ◽  
Gene Sets

Huntington disease (HD) is a neurodegenerative disorder caused by expanded CAG repeats in the Huntingtin gene. Results from previous studies have suggested that transcriptional dysregulation is one of the key mechanisms underlying striatal medium spiny neuron (MSN) degeneration in HD. However, some of the critical genes involved in HD etiology or pathology could be masked in a common expression profiling assay because of contamination with non-MSN cells. To gain insight into the MSN-specific gene expression changes in presymptomatic R6/2 mice, a common HD mouse model, here we used a transgenic fluorescent protein marker of MSNs for purification via FACS before profiling gene expression with gene microarrays and compared the results of this “FACS-array” with those obtained with homogenized striatal samples (STR-array). We identified hundreds of differentially expressed genes (DEGs) and enhanced detection of MSN-specific DEGs by comparing the results of the FACS-array with those of the STR-array. The gene sets obtained included genes ubiquitously expressed in both MSNs and non-MSN cells of the brain and associated with transcriptional regulation and DNA damage responses. We proposed that the comparative gene expression approach using the FACS-array may be useful for uncovering the gene cascades affected in MSNs during HD pathogenesis.

scholarly journals Neuronal over-expression of Oxr1 is protective against ALS-associated mutant TDP-43 mislocalisation in motor neurons and neuromuscular defects in vivo

2019 ◽  
Vol 28 (21) ◽  
pp. 3584-3599 ◽  
Author(s):  
Matthew G Williamson ◽  
Mattéa J Finelli ◽  
James N Sleigh ◽  
Amy Reddington ◽  
David Gordon ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Gene Encoding ◽  
Over Expression ◽  
Neuromuscular Abnormalities ◽  
And Function ◽  
Lateral Sclerosis

Abstract A common pathological hallmark of amyotrophic lateral sclerosis (ALS) and the related neurodegenerative disorder frontotemporal dementia, is the cellular mislocalization of transactive response DNA-binding protein 43 kDa (TDP-43). Additionally, multiple mutations in the TARDBP gene (encoding TDP-43) are associated with familial forms of ALS. While the exact role for TDP-43 in the onset and progression of ALS remains unclear, the identification of factors that can prevent aberrant TDP-43 localization and function could be clinically beneficial. Previously, we discovered that the oxidation resistance 1 (Oxr1) protein could alleviate cellular mislocalization phenotypes associated with TDP-43 mutations, and that over-expression of Oxr1 was able to delay neuromuscular abnormalities in the hSOD1G93A ALS mouse model. Here, to determine whether Oxr1 can protect against TDP-43-associated phenotypes in vitro and in vivo, we used the same genetic approach in a newly described transgenic mouse expressing the human TDP-43 locus harbouring an ALS disease mutation (TDP-43M337V). We show in primary motor neurons from TDP-43M337V mice that genetically-driven Oxr1 over-expression significantly alleviates cytoplasmic mislocalization of mutant TDP-43. We also further quantified newly-identified, late-onset neuromuscular phenotypes of this mutant line, and demonstrate that neuronal Oxr1 over-expression causes a significant reduction in muscle denervation and neuromuscular junction degeneration in homozygous mutants in parallel with improved motor function and a reduction in neuroinflammation. Together these data support the application of Oxr1 as a viable and safe modifier of TDP-43-associated ALS phenotypes.

Mutations in the ELA2 gene encoding neutrophil elastase are present in most patients with sporadic severe congenital neutropenia but only in some patients with the familial form of the disease

Blood ◽  
2001 ◽  
Vol 98 (9) ◽  
pp. 2645-2650 ◽  
Author(s):  
Phil J. Ancliff ◽  
Rosemary E. Gale ◽  
Ri Liesner ◽  
Ian M. Hann ◽  
David C. Linch
Keyword(s):  
Neutrophil Elastase ◽  
Autosomal Recessive ◽  
Autosomal Dominant ◽  
Autosomal Recessive Disorder ◽  
Severe Neutropenia ◽  
Base Substitution ◽  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia ◽  
Gene Encoding ◽  
Familial Form

Abstract Severe congenital neutropenia (SCN) was originally described as an autosomal recessive disorder. Subsequently, autosomal dominant and sporadic forms of the disease have been recognized. All forms are manifest by persistent severe neutropenia and recurrent bacterial infection. In contrast, cyclical hematopoiesis is characterized by periodic neutropenia inter-spaced with (near) normal neutrophil counts. Recently, linkage analysis on 13 affected pedigrees identified chromosome 19p13.3 as the likely position for mutations in cyclical hematopoiesis. Heterozygous mutations in the ELA2 gene encoding neutrophil elastase were detected in all families studied. Further work also demonstrated mutations in ELA2 in sporadic and autosomal dominant SCN. However, all mutations described to date are heterozygous and thus appear to act in a dominant fashion, which is inconsistent with an autosomal recessive disease. Therefore, the current study investigated whether mutations in ELA2could account for the disease phenotype in classical autosomal recessive SCN and in the sporadic and autosomal dominant types. All 5 exons of ELA2 and their flanking introns were studied in 18 patients (3 autosomal recessive, 5 autosomal dominant [from 3 kindreds], and 10 sporadic) using direct automated sequencing. No mutations were found in the autosomal recessive families. A point mutation was identified in 1 of 3 autosomal dominant families, and a base substitution was identified in 8 of 10 patients with the sporadic form, though 1 was subsequently shown to be a low-frequency polymorphism. These results suggest that mutations in ELA2are not responsible for classical autosomal recessive Kostmann syndrome but provide further evidence for the role of ELA2 in SCN.

scholarly journals Laforin, a dual-specificity phosphatase involved in Lafora disease, is phosphorylated at Ser25 by AMP-activated protein kinase

2011 ◽  
Vol 439 (2) ◽  
pp. 265-275 ◽  
Author(s):  
Carlos Romá-Mateo ◽  
Maria del Carmen Solaz-Fuster ◽  
José Vicente Gimeno-Alcañiz ◽  
Vikas V. Dukhande ◽  
Jordi Donderis ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Neurodegenerative Disorder ◽  
Critical Role ◽  
Glycogen Metabolism ◽  
Lafora Disease ◽  
Gene Encoding ◽  
Dual Specificity Phosphatase ◽  
Progressive Myoclonus Epilepsy ◽  
Dual Specificity ◽  
Amp Activated Protein Kinase

Lafora progressive myoclonus epilepsy [LD (Lafora disease)] is a fatal autosomal recessive neurodegenerative disorder caused by loss-of-function mutations in either the EPM2A gene, encoding the dual-specificity phosphatase laforin, or the EPM2B gene, encoding the E3-ubiquitin ligase malin. Previously, we and others showed that laforin and malin form a functional complex that regulates multiple aspects of glycogen metabolism, and that the interaction between laforin and malin is enhanced by conditions activating AMPK (AMP-activated protein kinase). In the present study, we demonstrate that laforin is a phosphoprotein, as indicated by two-dimensional electrophoresis, and we identify Ser25 as the residue involved in this modification. We also show that Ser25 is phosphorylated both in vitro and in vivo by AMPK. Lastly, we demonstrate that this residue plays a critical role for both the phosphatase activity and the ability of laforin to interact with itself and with previously established binding partners. The results of the present study suggest that phosphorylation of laforin-Ser25 by AMPK provides a mechanism to modulate the interaction between laforin and malin. Regulation of this complex is necessary to maintain normal glycogen metabolism. Importantly, Ser25 is mutated in some LD patients (S25P), and our results begin to elucidate the mechanism of disease in these patients.

Congenital Neuronal Ceroid Lipofuscinosis with a Novel CTSD Gene Mutation: A Rare Cause of Neonatal-Onset Neurodegenerative Disorder

2017 ◽  
Vol 49 (02) ◽  
pp. 150-153 ◽  
Author(s):  
K. Varvagiannis ◽  
S. Hanquinet ◽  
M. Billieux ◽  
R. De Luca ◽  
P. Rimensberger ◽  
...  
Keyword(s):  
Neurodegenerative Disorder ◽  
Age Of Onset ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Molecular Genetic ◽  
Bioinformatic Analysis ◽  
Neuronal Ceroid Lipofuscinoses ◽  
Gene Encoding ◽  
Functional Studies ◽  
Ceroid Lipofuscinosis ◽  
Similar Phenotype

AbstractNeuronal ceroid lipofuscinoses represent a heterogeneous group of early onset neurodegenerative disorders that are characterized by progressive cognitive and motor function decline, visual loss, and epilepsy. The age of onset has been historically used for the phenotypic classification of this group of disorders, but their molecular genetic delineation has now enabled a better characterization, demonstrating significant genetic heterogeneity even among individuals with a similar phenotype. The rare Congenital Neuronal Ceroid Lipofuscinosis (CLN10) caused by mutations in the CTSD gene encoding for cathepsin D is associated with a dramatic presentation with onset before or around birth. We report on a female born to consanguineous parents who presented at birth with severe neonatal encephalopathy with massive cerebral and cerebellar shrinking on magnetic resonance imaging. Whole exome sequencing with targeted bioinformatic analysis of a panel of genes associated with prenatal/perinatal onset of neurodegenerative disease was performed and revealed the presence of a novel homozygous in-frame deletion in CTSD. Additional functional studies further confirmed the pathogenic character of this variant and established the diagnosis of CLN10 in the patient.

scholarly journals Amyotrophic Lateral Sclerosis: The Most Common And Lethal Form Of Motor Neuron Disease-a Case Report From Middle East

2019 ◽  
Vol 09 (02) ◽  
pp. 156-158
Author(s):  
Waseem Mehmood Nizamani ◽  
Ameet Jesrani ◽  
Mujtaba Khan ◽  
Kalthoum Tlili ◽  
Nader Al Khuraish ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Clinical Presentation ◽  
Neurodegenerative Disorder ◽  
Signs And Symptoms ◽  
Corticospinal Tracts ◽  
Familial Form ◽  
Lateral Sclerosis ◽  
Made In

A neurodegenerative disorder which is fatal, rapidly progressive and has no effective treatment till date is amyotrophic lateral sclerosis. Almost 90% of all cases occur in the sporadic form, with the rest occurring in the familial form. It is a devastating disease leading to death within 3-5 years in most cases. The diagnosis of AML is difficult to made in spite of acknowledgment for 140 years. It is diagnosed by clinical presentation which is a combination of upper and lower motor neuron signs and electro diagnostic studies which gives information about diffuse motor axonal injury. This neurodegenerative disorder results in degeneration of corticospinal tracts and anterior horn cells and involving motor neurons of the cerebral cortex, brainstem, and spinal cord. There are a variable signs and symptoms of this disease, so the diagnosis is very important for the management and better outcome of the patients. Cause of death in these patients is usually respiratory failure

Mechanism and chain specificity of RNF216/TRIAD3, the ubiquitin ligase mutated in Gordon Holmes syndrome

2019 ◽  
Vol 28 (17) ◽  
pp. 2862-2873 ◽  
Author(s):  
Ramkumar Seenivasan ◽  
Thomas Hermanns ◽  
Tamara Blyszcz ◽  
Michael Lammers ◽  
Gerrit J K Praefcke ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Neurodegenerative Disorder ◽  
Hypogonadotropic Hypogonadism ◽  
Missense Mutations ◽  
Gene Encoding ◽  
Highly Active ◽  
Ubiquitin Ligase Activity ◽  
Catalytic Cysteine ◽  
Ubiquitin Binding Domain ◽  
E2 Enzymes

AbstractGordon Holmes syndrome (GDHS) is an adult-onset neurodegenerative disorder characterized by ataxia and hypogonadotropic hypogonadism. GDHS is caused by mutations in the gene encoding the RING-between-RING (RBR)-type ubiquitin ligase RNF216, also known as TRIAD3. The molecular pathology of GDHS is not understood, although RNF216 has been reported to modify several substrates with K48-linked ubiquitin chains, thereby targeting them for proteasomal degradation. We identified RNF216 in a bioinformatical screen for putative SUMO-targeted ubiquitin ligases and confirmed that a cluster of predicted SUMO-interaction motifs (SIMs) indeed recognizes SUMO2 chains without targeting them for ubiquitination. Surprisingly, purified RNF216 turned out to be a highly active ubiquitin ligase that exclusively forms K63-linked ubiquitin chains, suggesting that the previously reported increase of K48-linked chains after RNF216 overexpression is an indirect effect. The linkage-determining region of RNF216 was mapped to a narrow window encompassing the last two Zn-fingers of the RBR triad, including a short C-terminal extension. Neither the SIMs nor a newly discovered ubiquitin-binding domain in the central portion of RNF216 contributes to chain specificity. Both missense mutations reported in GDHS patients completely abrogate the ubiquitin ligase activity. For the R660C mutation, ligase activity could be restored by using a chemical ubiquitin loading protocol that circumvents the requirement for ubiquitin-conjugating (E2) enzymes. This result suggests Arg-660 to be required for the ubiquitin transfer from the E2 to the catalytic cysteine. Our findings necessitate a re-evaluation of the previously assumed degradative role of RNF216 and rather argue for a non-degradative K63 ubiquitination, potentially acting on SUMOylated substrates.

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