scholarly journals In-frame deletion in canine PITRM1 is associated with a severe early-onset epilepsy, mitochondrial dysfunction and neurodegeneration

2021 ◽  
Author(s):  
Marjo K. Hytönen ◽  
Riika Sarviaho ◽  
Christopher B. Jackson ◽  
Pernilla Syrjä ◽  
Tarja Jokinen ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Early Onset ◽  
Motor Coordination ◽  
Neuronal Degeneration ◽  
Amyloid Β ◽  
Homozygosity Mapping ◽  
Loss Of Function ◽  
Brain Disorder ◽  
Clinical Genetic ◽  
The Brain

AbstractWe investigated the clinical, genetic, and pathological characteristics of a previously unknown severe juvenile brain disorder in several litters of Parson Russel Terriers. The disease started with epileptic seizures at 6–12 weeks of age and progressed rapidly to status epilepticus and death or euthanasia. Histopathological changes at autopsy were restricted to the brain. There was severe acute neuronal degeneration and necrosis diffusely affecting the grey matter throughout the brain with extensive intraneuronal mitochondrial crowding and accumulation of amyloid-β (Aβ). Combined homozygosity mapping and genome sequencing revealed an in-frame 6-bp deletion in the nuclear-encoded pitrilysin metallopeptidase 1 (PITRM1) encoding for a mitochondrial protease involved in mitochondrial targeting sequence processing and degradation. The 6-bp deletion results in the loss of two amino acid residues in the N-terminal part of PITRM1, potentially affecting protein folding and function. Assessment of the mitochondrial function in the affected brain tissue showed a significant deficiency in respiratory chain function. The functional consequences of the mutation were modeled in yeast and showed impaired growth in permissive conditions and an impaired respiration capacity. Loss-of-function variants in human PITRM1 result in a childhood-onset progressive amyloidotic neurological syndrome characterized by spinocerebellar ataxia with behavioral, psychiatric and cognitive abnormalities. Homozygous Pitrm1-knockout mice are embryonic lethal, while heterozygotes show a progressive, neurodegenerative phenotype characterized by impairment in motor coordination and Aβ deposits. Our study describes a novel early-onset PITRM1-related neurodegenerative canine brain disorder with mitochondrial dysfunction, Aβ accumulation, and lethal epilepsy. The findings highlight the essential role of PITRM1 in neuronal survival and strengthen the connection between mitochondrial dysfunction and neurodegeneration.

scholarly journals In-frame deletion in canine PITRM1 is associated with a severe early-onset epilepsy, mitochondrial dysfunction and neurodegeneration

2021 ◽  
Author(s):  
Marjo K Hytönen ◽  
Riika Sarviaho ◽  
Christopher B Jackson ◽  
Pernilla Syrjä ◽  
Tarja Jokinen ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Early Onset ◽  
Motor Coordination ◽  
Neuronal Degeneration ◽  
Amyloid Β ◽  
Homozygosity Mapping ◽  
Loss Of Function ◽  
Brain Disorder ◽  
Clinical Genetic ◽  
The Brain

Abstract We investigated the clinical, genetic, and pathological characteristics of a previously unknown severe juvenile brain disorder in several litters of Parson Russel Terriers. The disease started with epileptic seizures at 6 to 12 weeks of age and progressed rapidly to status epilepticus and death or euthanasia. Histopathological changes at autopsy were restricted to the brain. There was severe acute neuronal degeneration and necrosis diffusely affecting the grey matter throughout the brain with extensive intraneuronal mitochondrial crowding and accumulation of amyloid-β (Aβ). Combined homozygosity mapping and genome sequencing revealed an in-frame 6-bp deletion in the nuclear-encoded pitrilysin metallopeptidase 1 (PITRM1) encoding for a mitochondrial protease involved in mitochondrial targeting sequence processing and degradation. The 6-bp deletion results in the loss of two amino acid residues in the N-terminal part of PITRM1, potentially affecting protein folding and function. Assessment of the mitochondrial function in the affected brain tissue showed a significant deficiency in respiratory chain function. The functional consequences of the mutation were modeled in yeast and showed impaired growth in permissive conditions and an impaired respiration capacity. Loss-of-function variants in human PITRM1 result in a childhood-onset progressive amyloidotic neurological syndrome characterized by spinocerebellar ataxia with behavioral, psychiatric and cognitive abnormalities. Homozygous Pitrm1-knockout mice are embryonic lethal, while heterozygotes show a progressive, neurodegenerative phenotype characterized by impairment in motor coordination and Aβ deposits. Our study describes a novel early-onset PITRM1-related neurodegenerative canine brain disorder with mitochondrial dysfunction, Aβ accumulation, and lethal epilepsy. The findings highlight the essential role of PITRM1 in neuronal survival and strengthen the connection between mitochondrial dysfunction and neurodegeneration.

scholarly journals Pathogenic STX3 variants affecting the retinal and intestinal transcripts cause an early-onset severe retinal dystrophy in microvillus inclusion disease subjects

2021 ◽  
Author(s):  
Andreas R. Janecke ◽  
Xiaoqin Liu ◽  
Rüdiger Adam ◽  
Sumanth Punuru ◽  
Arne Viestenz ◽  
...  
Keyword(s):  
Early Onset ◽  
Single Nucleotide Polymorphism Array ◽  
Outer Nuclear Layer ◽  
Retinal Dystrophy ◽  
Geographic Origin ◽  
Retinal Disease ◽  
Homozygosity Mapping ◽  
Rod Photoreceptor ◽  
Loss Of Function ◽  
Knockout Mouse Model

AbstractBiallelic STX3 variants were previously reported in five individuals with the severe congenital enteropathy, microvillus inclusion disease (MVID). Here, we provide a significant extension of the phenotypic spectrum caused by STX3 variants. We report ten individuals of diverse geographic origin with biallelic STX3 loss-of-function variants, identified through exome sequencing, single-nucleotide polymorphism array-based homozygosity mapping, and international collaboration. The evaluated individuals all presented with MVID. Eight individuals also displayed early-onset severe retinal dystrophy, i.e., syndromic—intestinal and retinal—disease. These individuals harbored STX3 variants that affected both the retinal and intestinal STX3 transcripts, whereas STX3 variants affected only the intestinal transcript in individuals with solitary MVID. That STX3 is essential for retinal photoreceptor survival was confirmed by the creation of a rod photoreceptor-specific STX3 knockout mouse model which revealed a time-dependent reduction in the number of rod photoreceptors, thinning of the outer nuclear layer, and the eventual loss of both rod and cone photoreceptors. Together, our results provide a link between STX3 loss-of-function variants and a human retinal dystrophy. Depending on the genomic site of a human loss-of-function STX3 variant, it can cause MVID, the novel intestinal-retinal syndrome reported here or, hypothetically, an isolated retinal dystrophy.

scholarly journals Early-onset and Robust Cerebral Microvascular Accumulation of Amyloid β-Protein in Transgenic Mice Expressing Low Levels of a Vasculotropic Dutch/Iowa Mutant Form of Amyloid β-Protein Precursor

2004 ◽  
Vol 279 (19) ◽  
pp. 20296-20306 ◽  
Author(s):  
Judianne Davis ◽  
Feng Xu ◽  
Rashid Deane ◽  
Galina Romanov ◽  
Mary Lou Previti ◽  
...  
Keyword(s):  
Early Onset ◽  
Amyloid Β ◽  
Enzyme Linked Immunosorbent Assay ◽  
Mutant Form ◽  
Amyloid Β Protein ◽  
Pathological Feature ◽  
High Association ◽  
Cerebral Microvessels ◽  
Β Protein ◽  
The Brain

Cerebrovascular deposition of amyloid β-protein (Aβ) is a common pathological feature of Alzheimer's disease and related disorders. In particular, the Dutch E22Q and Iowa D23N mutations in Aβ cause familial cerebrovascular amyloidosis with abundant diffuse amyloid plaque deposits. Both of these charge-altering mutations enhance the fibrillogenic and pathogenic properties of Aβin vitro. Here, we describe the generation of several transgenic mouse lines (Tg-SwDI) expressing human neuronal Aβ precursor protein (AβPP) harboring the Swedish K670N/M671L and vasculotropic Dutch/Iowa E693Q/D694N mutations under the control of the mouse Thy1.2 promoter. Tg-SwDI mice expressed transgenic human AβPP only in the brain, but at levels below those of endogenous mouse AβPP. Despite the paucity of human AβPP expression, quantitative enzyme-linked immunosorbent assay measurements revealed that Tg-SwDI mice developed early-onset and robust accumulation of Aβ in the brain with high association with isolated cerebral microvessels. Tg-SwDI mice exhibited striking perivascular/vascular Aβ deposits that markedly increased with age. The vascular Aβ accumulations were fibrillar, exhibiting strong thioflavin S staining, and occasionally presented signs of microhemorrhage. In addition, numerous largely diffuse, plaque-like structures were observed starting at 3 months of age.In vivotransport studies demonstrated that Dutch/Iowa mutant Aβ was more readily retained in the brain compared with wild-type Aβ. These results with Tg-SwDI mice demonstrate that overexpression of human AβPP is not required for early-onset and robust accumulation of both vascular and parenchymal Aβ in mouse brain.

scholarly journals Might Fibroblasts from Patients with Alzheimer’s Disease Reflect the Brain Pathology? A Focus on the Increased Phosphorylation of Amyloid Precursor Protein Tyr682 Residue

2021 ◽  
Vol 11 (1) ◽  
pp. 103
Author(s):  
Filomena Iannuzzi ◽  
Vincenza Frisardi ◽  
Lucio Annunziato ◽  
Carmela Matrone
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Neurodegenerative Disorder ◽  
Neuronal Degeneration ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Diagnostic Strategy ◽  
Peripheral Cells ◽  
The Brain

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder with no cure and no effective diagnostic criteria. The greatest challenge in effectively treating AD is identifying biomarkers specific for each patient when neurodegenerative processes have not yet begun, an outcome that would allow the design of a personalised therapeutic approach for each patient and the monitoring of the therapeutic response during the treatment. We found that the excessive phosphorylation of the amyloid precursor protein (APP) Tyr682 residue on the APP 682YENPTY687 motif precedes amyloid β accumulation and leads to neuronal degeneration in AD neurons. We proved that Fyn tyrosine kinase elicits APP phosphorylation on Tyr682 residue, and we reported increased levels of APP Tyr682 and Fyn overactivation in AD neurons. Here, we want to contemplate the possibility of using fibroblasts as tools to assess APP Tyr682 phosphorylation in AD patients, thus making the changes in APP Tyr682 phosphorylation levels a potential diagnostic strategy to detect early pathological alterations present in the peripheral cells of AD patients’ AD brains.

scholarly journals Fluoxetine increases brain MeCP2 immuno-positive cells in a female Mecp2 heterozygous mouse model of Rett syndrome through endogenous serotonin

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Claudia Villani ◽  
Mirjana Carli ◽  
Anna Maria Castaldo ◽  
Giuseppina Sacchetti ◽  
Roberto William Invernizzi
Keyword(s):  
Prefrontal Cortex ◽  
Rett Syndrome ◽  
Motor Coordination ◽  
Antidepressant Drug ◽  
Brain Regions ◽  
Loss Of Function ◽  
Heterozygous Mouse ◽  
Skill Deficit ◽  
Second Year ◽  
The Brain

AbstractMotor skill deficit is a common and invalidating symptom of Rett syndrome (RTT), a rare disease almost exclusively affecting girls during the first/second year of life. Loss-of-function mutations of the methyl-CpG-binding protein2 (MECP2; Mecp2 in rodents) gene is the cause in most patients. We recently found that fluoxetine, a selective serotonin (5-HT) reuptake inhibitor and antidepressant drug, fully rescued motor coordination deficits in Mecp2 heterozygous (Mecp2 HET) mice acting through brain 5-HT. Here, we asked whether fluoxetine could increase MeCP2 expression in the brain of Mecp2 HET mice, under the same schedule of treatment improving motor coordination. Fluoxetine increased the number of MeCP2 immuno-positive (MeCP2+) cells in the prefrontal cortex, M1 and M2 motor cortices, and in dorsal, ventral and lateral striatum. Fluoxetine had no effect in the CA3 region of the hippocampus or in any of the brain regions of WT mice. Inhibition of 5-HT synthesis abolished the fluoxetine-induced rise of MeCP2+ cells. These findings suggest that boosting 5-HT transmission is sufficient to enhance the expression of MeCP2 in several brain regions of Mecp2 HET mice. Fluoxetine-induced rise of MeCP2 could potentially rescue motor coordination and other deficits of RTT.

scholarly journals DPP6 gene in European American Alzheimer’s Disease

2020 ◽  
Author(s):  
Laxmi Kirola ◽  
John P. Budde ◽  
Fengxian Wang ◽  
Joanne Norton ◽  
John C. Morris ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Early Onset ◽  
Late Onset ◽  
Transmembrane Protein ◽  
Loss Of Function ◽  
Sequencing Project ◽  
Or Gene ◽  
The Brain ◽  
Significant Statistical Association ◽  
Hispanic White

AbstractDPP6 encodes a transmembrane protein that expresses highly in the hippocampal regions of the brain and regulates dendritic excitability. Recently, rare and loss of function variants were reported in DPP6 and further demonstrated to be associated with early onset Alzheimer Disease (AD) and frontotemporal dementia. We performed single variant and gene-based analyses in three non-Hispanic white cohorts: a familial late onset AD (cases=1212, controls=341), an unrelated early onset AD (cases=1385, controls=3864) and in the unrelated Alzheimer disease sequencing project (ADSP, cases=5679, controls=4601). Neither single variant or gene-based analysis revealed any significant statistical association of DPP6 variants with the risk for AD in the cohorts examined.

scholarly journals ABCA7 haplodeficiency disturbs microglial immune responses in the mouse brain

2019 ◽  
Vol 116 (47) ◽  
pp. 23790-23796 ◽  
Author(s):  
Tomonori Aikawa ◽  
Yingxue Ren ◽  
Yu Yamazaki ◽  
Masaya Tachibana ◽  
Madeleine R. Johnson ◽  
...  
Keyword(s):  
Immune Responses ◽  
Acute Inflammation ◽  
Treatment Strategies ◽  
Amyloid Β ◽  
Loss Of Function ◽  
Premature Termination Codons ◽  
Increased Risk ◽  
Proinflammatory Responses ◽  
The Brain ◽  
Insight Into

Carrying premature termination codons in 1 allele of the ABCA7 gene is associated with an increased risk for Alzheimer’s disease (AD). While the primary function of ABCA7 is to regulate the transport of phospholipids and cholesterol, ABCA7 is also involved in maintaining homeostasis of the immune system. Since inflammatory pathways causatively or consequently participate in AD pathogenesis, we studied the effects of Abca7 haplodeficiency in mice on brain immune responses under acute and chronic conditions. When acute inflammation was induced through peripheral lipopolysaccharide injection in control or heterozygous Abca7 knockout mice, partial ABCA7 deficiency diminished proinflammatory responses by impairing CD14 expression in the brain. On breeding to AppNL-G-F knockin mice, we observed increased amyloid-β (Aβ) accumulation and abnormal endosomal morphology in microglia. Taken together, our results demonstrate that ABCA7 loss of function may contribute to AD pathogenesis by altering proper microglial responses to acute inflammatory challenges and during the development of amyloid pathology, providing insight into disease mechanisms and possible treatment strategies.

Metallic prions

2004 ◽  
Vol 71 ◽  
pp. 193-202 ◽  
Author(s):  
David R Brown
Keyword(s):  
Prion Protein ◽  
Binding Capacity ◽  
Normal Function ◽  
Transmissible Spongiform Encephalopathies ◽  
Published Data ◽  
Normal Brain ◽  
Copper Binding ◽  
Loss Of Function ◽  
Spongiform Encephalopathies ◽  
The Brain

Prion diseases, also referred to as transmissible spongiform encephalopathies, are characterized by the deposition of an abnormal isoform of the prion protein in the brain. However, this aggregated, fibrillar, amyloid protein, termed PrPSc, is an altered conformer of a normal brain glycoprotein, PrPc. Understanding the nature of the normal cellular isoform of the prion protein is considered essential to understanding the conversion process that generates PrPSc. To this end much work has focused on elucidation of the normal function and activity of PrPc. Substantial evidence supports the notion that PrPc is a copper-binding protein. In conversion to the abnormal isoform, this Cu-binding activity is lost. Instead, there are some suggestions that the protein might bind other metals such as Mn or Zn. PrPc functions currently under investigation include the possibility that the protein is involved in signal transduction, cell adhesion, Cu transport and resistance to oxidative stress. Of these possibilities, only a role in Cu transport and its action as an antioxidant take into consideration PrPc's Cu-binding capacity. There are also more published data supporting these two functions. There is strong evidence that during the course of prion disease, there is a loss of function of the prion protein. This manifests as a change in metal balance in the brain and other organs and substantial oxidative damage throughout the brain. Thus prions and metals have become tightly linked in the quest to understand the nature of transmissible spongiform encephalopathies.

Fisiopatología de la hidrocefália idiopática de presión normal (parte 3): sistemaa glinfático

2016 ◽  
Vol 21 (2) ◽  
pp. 28-37
Author(s):  
Oscar Solís-Salgado ◽  
José Luis López-Payares ◽  
Mauricio Ayala-González
Keyword(s):  
Amyloid Beta ◽  
Interstitial Fluid ◽  
Amyloid Β ◽  
Bulk Flow ◽  
Polyethylene Glycols ◽  
Brain Interstitial Fluid ◽  
El Sistema ◽  
Arterial Pulsation ◽  
The Brain

Las vías de drenaje solutos del sistema nervioso central (SNC) participan en el recambio de liquido intersticial con el líquido cefalorraquídeo (LIT-LCR), generando un estado de homeostasis. Las alteraciones dentro de este sistema homeostático afectará la eliminación de solutos del espacio intersticial (EIT) como el péptido βa y proteína tau, los cuales son sustancias neurotóxicas para el SNC. Se han utilizado técnicas experimentales para poder analizar el intercambio LIT-LCR, las cuales revelan que este intercambio tiene una estructura bien organizada. La eliminación de solutos del SNC no tiene una estructura anatómica propiamente, se han descubierto vías de eliminación de solutos a través de marcadores florecentes en el espacio subaracnoideo, cisternas de la base y sistema ventricular que nos permiten observar una serie de vías ampliamente distribuidas en el cerebro. El LCR muestra que tiene una función linfática debido a su recambio con el LIT a lo largo de rutas paravasculares. Estos espacios que rodean la superficie arterial así como los espacios de Virchow-Robin y el pie astrocitico junto con la AQP-4, facilitan la entrada de LCR para-arterial y el aclaramiento de LIT para-venoso dentro del cerebro. El flujo y dirección que toma el LCR por estas estructuras, es conducido por la pulsación arterial. Esta función será la que finalmente llevara a la eliminación de estas sustancias neurotóxicas. En base a la dependencia de este flujo para la eliminación de sustancias se propone que el sistema sea llamado “ la Vía Glinfática”. La bibliografía así como las limitaciones que se encuentran en esta revisión están dadas por la metodología de búsqueda que ha sido realizada principalmente en PubMed utilizando los siguientes términos Mesh: Cerebral Arterial Pulsation, the brain via paravascular, drainage of amyloid-beta, bulk flow of brain interstitial fluid, radiolabeled polyethylene glycols and albumin, amyloid-β, the perivascular astroglial sheath, Brain Glymphatic Transport.

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