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Mitochondrial ferritin (FtMt) is an endogenous iron-storage protein localized in the mitochondria. FtMt is mainly observed in restricted tissues, such as those in the testis, islets of Langerhans, and brain. Further, it may protect cells from oxidative stress in neurodegenerative diseases, including Alzheimer's disease and progressive supranuclear palsy. However, the role of FtMt in Parkinson's disease (PD) remains unclear. Therefore, the current study investigated the localization and expression level of FtMt in the midbrain of patients with PD and healthy controls using immunohistochemical techniques. FtMt immunoreactivity was mainly detected in dopaminergic neurons in the substantia nigra pars compacta (SNc) in both healthy controls and patients with PD. In addition, FtMt-positive particles were observed outside the dopaminergic neurons in patients with PD. Based on a quantitative comparison, patients with PD had a significantly upregulated FtMt immunoreactivity in dopaminergic neurons than healthy controls. Our result might be helpful in future studies on the role of FtMt in PD.
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In the pathogenesis of Alzheimer's disease (AD), highly neurotoxic amyloid-ß (Aß) oligomers appear early, they are thus considered to be deeply involved in the onset of Alzheimer's disease. However, Aß oligomer visualization is challenging in human tissues due to their multiple forms (e.g., low- and high-molecular-weight oligomers, including protofibrils) as well as their tendency to rapidly change forms and aggregate. In this review, we present two visualization approaches for Aß oligomers in tissues: an immunohistochemical (using the monoclonal antibody TxCo1 against toxic Aß oligomer conformers) and imaging mass spectrometry using the small chemical Shiga-Y51 that specifically binds Aß oligomers. TxCo1 immunohistochemistry revealed Aß oligomer distributions in postmortem human brains with AD. Using Shiga-Y51, imaging mass spectrometry revealed Aß oligomer distributions in the brain of a transgenic mouse model for AD. These two methods would potentially contribute to elucidating the pathological mechanisms underlying AD.
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Since amyloid ß (Aß) oligomers are more cytotoxic than fibrils, various dimer models have been synthesized. We focused on the C-terminal region that could form a hydrophobic core in the aggregation process and identified a toxic conformer-restricted dimer model (E22P,G38DAP-Aß40 dimer) with an l,l-2,6-diaminopimelic acid linker (n = 3) at position 38, which exhibited moderate cytotoxicity. We synthesized four additional linkers (n = 2, 4, 5, 7) to determine the most appropriate distance between the two Aß40 monomers for a toxic dimer model. Each di-Fmoc-protected two-valent amino acid was synthesized from a corresponding dialdehyde or cycloalkene followed by ozonolysis, using a Horner-Wadsworth-Emmons reaction and asymmetric hydrogenation. Then, the corresponding Aß40 dimer models with these linkers at position 38 were synthesized using the solid-phase Fmoc strategy. Their cytotoxicity toward SH-SY5Y cells suggested that the shorter the linker length, the stronger the cytotoxicity. Particularly, the E22P,G38DAA-Aß40 dimer (n = 2) formed protofibrillar aggregates and exhibited the highest cytotoxicity, equivalent to E22P-Aß42, the most cytotoxic analogue of Aß42. Ion mobility-mass spectrometry (IM-MS) measurement indicated that all dimer models except the E22P,G38DAA-Aß40 dimer existed as stable oligomers (12-24-mer). NativePAGE analysis supported the IM-MS data, but larger oligomers (30-150-mer) were also detected after a 24 h incubation. Moreover, E22P,G38DAA-Aß40, E22P,G38DAP-Aß40, and E22P,G38DAZ-Aß40 (n = 5) dimers suppressed long-term potentiation (LTP). Overall, the ability to form fibrils with cross ß-sheet structures was key to achieving cytotoxicity, and forming stable oligomers less than 150-mer did not correlate with cytotoxicity and LTP suppression.
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Enfermedad de Alzheimer , Cicloparafinas , Neuroblastoma , Ozono , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Ácido Diaminopimélico , Humanos , Fragmentos de Péptidos/metabolismoRESUMEN
Oligomers of the amyloid ß (Aß) protein play a critical role in the pathogenesis of Alzheimer's disease. However, their heterogeneity and lability deter the identification of their tertiary structures and mechanisms of action. Aß trimers and Aß dimers may represent the smallest aggregation unit with cytotoxicity. Although propeller-type trimer models of E22P-Aß40 tethered by an aromatic linker have recently been synthesized, they unexpectedly exhibited little cytotoxicity. To increase the flexibility of trimeric propeller-type models, we designed and synthesized trimer models with an alkyl linker, tert-butyltris-l-alanine (tButA), at position 36 or 38. In addition, we synthesized two parallel-type trimer models tethered at position 38 using alkyl linkers of different lengths, α,α-di-l-norvalyl-l-glycine (di-nV-Gly) and α,α-di-l-homonorleucyl-l-glycine (di-hnL-Gly), based on the previously reported toxic dimer model. The propeller-type E22P,V36tButA-Aß40 trimer (4), which was designed to mimic the C-terminal anti-parallel ß-sheet structures proposed by the structural analysis of 150 kDa oligomers of Aß42, and the parallel-type E22P,G38di-nV-Gly-Aß40 trimer (6) showed significant cytotoxicity against SH-SY5Y cells and aggregative ability to form protofibrillar species. In contrast, the E22P,G38tButA-Aß40 trimer (5) and E22P,G38di-hnL-Gly-Aß40 trimer (7) exhibited weak cytotoxicity, though they formed quasi-stable oligomers observed by ion mobility-mass spectrometry and native polyacrylamide gel electrophoresis. These results suggest that 4 and 6 could have some phase of the structure of toxic Aß oligomers with a C-terminal hydrophobic core and that the conformation and/or aggregation process rather than the formation of stable oligomers contribute to the induction of cytotoxicity.
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Enfermedad de Alzheimer , Neuroblastoma , Enfermedad de Alzheimer/metabolismo , Amiloide , Péptidos beta-Amiloides/metabolismo , Glicina , Humanos , Fragmentos de Péptidos/metabolismoRESUMEN
Amyloid ß (Aß) oligomers play a critical role in the pathology of Alzheimer's disease. Recently, we reported that a conformation-restricted Aß42 with an intramolecular disulfide bond through cysteine residues at positions 17/28 formed stable oligomers with potent cytotoxicity. To further optimize this compound as a toxic conformer model, we synthesized three analogues with a combination of cysteine and homocysteine at positions 17/28. The analogues with Cys-Cys, Cys-homoCys, or homoCys-Cys, but not the homoCys-homoCys analogue, exhibited potent cytotoxicity against SH-SY5Y and THP-1 cells even at 10â nM. In contrast, the cytotoxicity of conformation-restricted analogues at positions 16/29 or 18/27 was significantly weaker than that of wild-type Aß42. Furthermore, thioflavin-T assay, non-denaturing gel electrophoresis, and morphological studies suggested that the majority of these conformation-restricted analogues exists in an oligomeric state in cell culture medium, indicating that the toxic conformation of Aß42, rather than the oligomeric state, is essential to induce cytotoxicity.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Enfermedad de Alzheimer/patología , Amiloide/química , Péptidos beta-Amiloides/química , Péptidos beta-Amiloides/toxicidad , Cisteína , Disulfuros/química , Humanos , Fragmentos de Péptidos/química , Fragmentos de Péptidos/toxicidadRESUMEN
Characterization of amyloid ß (Aß) oligomers, the transition species present prior to the formation of Aß fibrils and that have cytotoxicity, has become one of the major topics in the investigations of Alzheimer's disease (AD) pathogenesis. However, studying pathophysiological properties of Aß oligomers is challenging due to the instability of these protein complexes in vitro. Here, we report that conformation-restricted Aß42 with an intramolecular disulfide bond at positions 17 and 28 (SS-Aß42) formed stable Aß oligomers in vitro. Thioflavin T binding assays, nondenaturing gel electrophoresis, and morphological analyses revealed that SS-Aß42 maintained oligomeric structure, whereas wild-type Aß42 and the highly aggregative Aß42 mutant with E22P substitution (E22P-Aß42) formed Aß fibrils. In agreement with these observations, SS-Aß42 was more cytotoxic compared to the wild-type and E22P-Aß42 in cell cultures. Furthermore, we developed a monoclonal antibody, designated TxCo-1, using the toxic conformation of SS-Aß42 as immunogen. X-ray crystallography of the TxCo-1/SS-Aß42 complex, enzyme immunoassay, and immunohistochemical studies confirmed the recognition site and specificity of TxCo-1 to SS-Aß42. Immunohistochemistry with TxCo-1 antibody identified structures resembling senile plaques and vascular Aß in brain samples of AD subjects. However, TxCo-1 immunoreactivity did not colocalize extensively with Aß plaques identified with conventional Aß antibodies. Together, these findings indicate that Aß with a turn at positions 22 and 23, which is prone to form Aß oligomers, could show strong cytotoxicity and accumulated in brains of AD subjects. The SS-Aß42 and TxCo-1 antibody should facilitate understanding of the pathological role of Aß with toxic conformation in AD.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Amiloide , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Humanos , Fragmentos de Péptidos , Placa AmiloideRESUMEN
This paper examines the problem of diffeomorphic image registration in the presence of differing image intensity profiles and sparsely sampled, missing, or damaged tissue. Our motivation comes from the problem of aligning 3D brain MRI with 100-micron isotropic resolution to histology sections at 1 × 1 × 1,000-micron resolution with multiple varying stains. We pose registration as a penalized Bayesian estimation, exploiting statistical models of image formation where the target images are modeled as sparse and noisy observations of the atlas. In this injective setting, there is no assumption of symmetry between atlas and target. Cross-modality image matching is achieved by jointly estimating polynomial transformations of the atlas intensity. Missing data is accommodated via a multiple atlas selection procedure where several atlas images may be of homogeneous intensity and correspond to "background" or "artifact." The two concepts are combined within an Expectation-Maximization algorithm, where atlas selection posteriors and deformation parameters are updated iteratively and polynomial coefficients are computed in closed form. We validate our method with simulated images, examples from neuropathology, and a standard benchmarking dataset. Finally, we apply it to reconstructing digital pathology and MRI in standard atlas coordinates. By using a standard convolutional neural network to detect tau tangles in histology slices, this registration method enabled us to quantify the 3D density distribution of tauopathy throughout the medial temporal lobe of an Alzheimer's disease postmortem specimen.
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Objectives Despite being pathologically benign, jugular foramen meningioma (JFM) may be locally aggressive and spread in three compartments. Because of the complex anatomical location, radical removal of JFM usually causes serious morbidity through lower cranial nerve (LCN) deficits. To accomplish long-standing tumor control with good functional outcomes, we report function-preserving multimodal treatment (FMT) for JFM, comprising the combination of intradural tumor removal with the preservation of LCN function and stereotactic radiosurgery (RS) for the residual tumor. Materials This study investigated six JFM patients (five women, one man). Preoperatively, five patients showed no LCN sign. Results All patients underwent function-preserving retrosigmoid intradural tumor removal, and no patient developed new LCN deficit. Three patients underwent RS for the residual tumor at 8 to 12 months after surgery. After RS, all three tumors were controlled. No patients showed tumor recurrence or new LCN deficits in the follow-up period (2 months to 8 years). Conclusion FMT for JFMs can accomplish long-standing tumor control with excellent functional outcomes.
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INTRODUCTION: Primary age-related tauopathy (PART) is a recently described entity that can cause cognitive impairment in the absence of Alzheimer's disease (AD). Here, we compared neuropathological features, tau haplotypes, apolipoprotein E (APOE) genotypes, and cognitive profiles in age-matched subjects with PART and AD pathology. METHODS: Brain autopsies (n = 183) were conducted on participants 85 years and older from the Baltimore Longitudinal Study of Aging and Johns Hopkins Alzheimer's Disease Research Center. Participants, normal at enrollment, were followed with periodic cognitive evaluations until death. RESULTS: Compared with AD, PART subjects showed significantly slower rates of decline on measures of memory, language, and visuospatial performance. They also showed lower APOE ε4 allele frequency (4.1% vs. 17.6%, P = .0046). DISCUSSION: Our observations suggest that PART is separate from AD and its distinction will be important for the clinical management of patients with cognitive impairment and for public health care planning.
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Envejecimiento/patología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Disfunción Cognitiva/genética , Neuropatología , Tauopatías/genética , Anciano de 80 o más Años , Apolipoproteína E4/genética , Autopsia , Baltimore , Encéfalo , Genotipo , Humanos , Estudios Longitudinales , Memoria , Pruebas NeuropsicológicasRESUMEN
Amyloid ß (Aß) plays a critical role in the pathogenesis of Alzheimer's disease. Nevertheless, its distribution and clearance before Aß plaque formation needs to be elucidated. Using an optimized immunofluorescent staining method, we examined the distribution of Aß in the post-mortem parietal cortex of 35 subjects, 30 to 65 years of age, APOE ε3/ε3, without AD lesions. We used 11A1, an antibody against an Aß conformer which forms neurotoxic oligomers. 11A1 immunoreactivity (IR) was present in cortical neurons, pericapillary spaces, astrocytes and the extracellular compartment at 30 years of age. The percentage of neurons with 11A1 IR did not change with age, but the number and percentage of astrocytes with 11A1 IR gradually increased. Notably, the percentage of pericapillary spaces labeled with 11A1 IR declined significantly in the 5th decade of the life, at the same time that 11A1 IR increased in the extracellular space. Our findings indicate that the Aß toxic conformer is normally present in various cell types and brain parenchyma, and appears to be constitutively produced, degraded, and cleared from the inferior parietal cortex. The decrease in pericapillary Aß and the concomitant increase of extracellular Aß may reflect an age-associated impairment in Aß clearance from the brain.
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Péptidos beta-Amiloides/toxicidad , Lóbulo Parietal/metabolismo , Placa Amiloide/patología , Adulto , Anciano , Anticuerpos/metabolismo , Astrocitos/metabolismo , Femenino , Humanos , Masculino , Microglía/metabolismo , Persona de Mediana Edad , Neuronas/metabolismo , Placa Amiloide/metabolismoRESUMEN
Sporadic Alzheimer's disease (AD) usually presents clinically after 65 years of age, but its pathological changes begin decades earlier. We examined for AD pathology in the postmortem brains of 431 of subjects aged 30-65 years not clinically characterized. Among 40-49 year olds, 15% showed diffuse amyloid ß (Aß) plaques, with a prevalence of 80% in ApoE4/E4, 42% in E4/E3, and <1% in E3/E3 subjects. Aß deposits appeared after age 49 years in subjects with E3/E3 genotypes. Neuritic plaques first appeared after age 50 years and increased steadily with age in all genotypes. Insoluble Aß42 levels were highest in parietal, temporal, and frontal lobes, but barely detectable in precuneus. Tau lesions were present in the hippocampus and entorhinal cortex in 7% of subjects aged <40 years and increased steadily with age reaching near 70% in the 60- to 65-year age group. In the locus coeruleus, tau lesions were present in 72% of subjects aged 31-40 years and 94% in the 41- to 50-year age group. Both Aß and tau lesions are present in the brains of young individuals decades before the age of clinical onset of AD. Aß lesions closely correlate with the ApoE4 allele and appear as the earliest event in the development of senile plaques.
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Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Apolipoproteínas E/genética , Encéfalo/fisiología , Adulto , Anciano , Enfermedad de Alzheimer/metabolismo , Encéfalo/metabolismo , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Ovillos Neurofibrilares/patología , Placa Amiloide/patología , Proteínas tau/metabolismoRESUMEN
Our knowledge of how genetic risk variants contribute to psychiatric disease is mainly limited to neurons. However, the mechanisms whereby the same genetic risk factors could affect the physiology of glial cells remain poorly understood. We studied the role of a psychiatric genetic risk factor, Disrupted-In-Schizophrenia-1 (DISC1), in metabolic functions of astrocytes. We evaluated the effects of knockdown of mouse endogenous DISC1 (DISC1-KD) and expression of a dominant-negative, C-terminus truncated human DISC1 (DN-DISC1) on the markers of energy metabolism, including glucose uptake and lactate production, in primary astrocytes and in mice with selective expression of DN-DISC1 in astrocytes. We also assessed the effects of lactate treatment on altered affective behaviors and impaired spatial memory in DN-DISC1 mice. Both DISC1-KD and DN-DISC1 comparably decreased mRNA and protein levels of glucose transporter 4 and glucose uptake by primary astrocytes. Decreased glucose uptake was associated with reduced oxidative phosphorylation and glycolysis as well as diminished lactate production in vitro and in vivo. No significant effects of DISC1 manipulations in astrocytes were observed on expression of the subunits of the electron transport chain complexes or mitofilin, a neuronal DISC1 partner. Lactate treatment rescued the abnormal behaviors in DN-DISC1 male and female mice. Our results suggest that DISC1 may be involved in the regulation of lactate production in astrocytes to support neuronal activity and associated behaviors. Abnormal expression of DISC1 in astrocytes and resulting abnormalities in energy supply may be responsible for aspects of mood and cognitive disorders observed in patients with major psychiatric illnesses.
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Astrocitos/metabolismo , Ácido Láctico/metabolismo , Trastornos Mentales/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Animales , Conducta Animal , Metabolismo Energético , Técnicas de Silenciamiento del Gen , Glucosa/metabolismo , Humanos , Potencial de la Membrana Mitocondrial , Trastornos Mentales/genética , Ratones , Ratones Transgénicos , Proteínas del Tejido Nervioso/genéticaRESUMEN
Guanine nucleotide-binding proteins (G proteins) act as molecular switches to regulate many fundamental cellular processes. The lipid modification, palmitoylation, can be considered as a key factor for proper G protein function and plasma membrane localization. In Dictyostelium discoidum, Gα2 is essential for the chemotactic response to cAMP in their developmental life cycle. However, the regulation of Gα2 with respect to palmitoylation, activation and Gßγ association is less clear. In this study, Gα2 is shown to be palmitoylated on Cys-4 by [3 H]palmitate labeling. Loss of this palmitoylation site results in redistribution of Gα2 within the cell and poor D. discoideum development. Cellular re-localization is also observed for activated Gα2. In the membrane fraction, Gα2-wt (YFP) is highly enriched in a low-density membrane fraction, which is palmitoylation-dependent. Activated Gα2 monomer and heterotrimer are shifted to two different higher-density fractions. These results broaden our understanding of how G protein localization and function are regulated inside the cells.
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Dictyostelium/enzimología , Subunidades alfa de la Proteína de Unión al GTP/metabolismo , Lipoilación/fisiología , Proteínas Protozoarias/metabolismoRESUMEN
Abnormal accumulation of TDP-43 into cytoplasmic or nuclear inclusions with accompanying nuclear clearance, a common pathology initially identified in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), has also been found in Alzheimer' disease (AD). TDP-43 serves as a splicing repressor of nonconserved cryptic exons and that such function is compromised in brains of ALS and FTD patients, suggesting that nuclear clearance of TDP-43 underlies its inability to repress cryptic exons. However, whether TDP-43 cytoplasmic aggregates are a prerequisite for the incorporation of cryptic exons is not known. Here, we assessed hippocampal tissues from 34 human postmortem brains including cases with confirmed diagnosis of AD neuropathologic changes along with age-matched controls. We found that cryptic exon incorporation occurred in all AD cases exhibiting TDP-43 pathology. Furthermore, incorporation of cryptic exons was observed in the hippocampus when TDP-43 inclusions was restricted only to the amygdala, the earliest stage of TDP-43 progression. Importantly, cryptic exon incorporation could be detected in AD brains lacking TDP-43 inclusion but exhibiting nuclear clearance of TDP-43. These data supports the notion that the functional consequence of nuclear depletion of TDP-43 as determined by cryptic exon incorporation likely occurs as an early event of TDP-43 proteinopathy and may have greater contribution to the pathogenesis of AD than currently appreciated. Early detection and effective repression of cryptic exons in AD patients may offer important diagnostic and therapeutic implications for this devastating illness of the elderly.
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Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Encéfalo/metabolismo , Encéfalo/patología , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/genética , Núcleo Celular/metabolismo , Núcleo Celular/patología , Estudios de Cohortes , Exones , Femenino , Humanos , Inmunohistoquímica , Masculino , Neuronas/metabolismo , Neuronas/patología , Proteinopatías TDP-43/metabolismo , Proteinopatías TDP-43/patologíaRESUMEN
The amygdala has attracted considerable research interest because of its potential involvement in various neuropsychiatric disorders. Recently, attempts have been made using magnetic resonance imaging (MRI) to evaluate the integrity of the axonal connections to and from the amygdala under pathological conditions. Although amygdalar pathways have been studied extensively in animal models, anatomical references for the human brain are limited to histology-based resources from a small number of slice locations, orientations and annotations. In the present study, we performed high-resolution (250 µm) MRI of postmortem human brains followed by serial histology sectioning. The histology data were used to identify amygdalar pathways, and the anatomical delineation of the assigned structures was extended into 3D using the MRI data. We were able to define the detailed anatomy of the stria terminalis and amygdalofugal pathway, as well as the anatomy of the nearby basal forebrain areas, including the substantia innominata. The present results will help us understand in detail the white matter structures associated with the amygdala, and will serve as an anatomical reference for the design of in vivo MRI studies and interpretation of their data.
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PURPOSE: To investigate B0 -field-orientation dependent white matter contrast in the human brainstem based on R2 * and frequency difference (Δf) mapping from gradient echo (GRE) imaging at 11.7T. METHODS: Multi-echo GRE data were acquired from two fixed human brainstem specimens at multiple orientations with respect to the static B0 field. The B0 -orientation dependent modulation curves of R2 * and Δf measurements between short and long echo time regimes were used to reconstruct maps of three-dimensional (3D) white matter orientation vectors. The results were compared with maps from diffusion MRI, susceptibility tensor imaging, and histological staining of the same specimens. RESULTS: R2 * and Δf maps demonstrated distinct and significant contrast modulation between the corticospinal tract (CST) and transverse pontine fibers (TPF) dependent on B0 orientation. Interleaved fiber orientations of the CST and TPF could be sensitively resolved based on field-orientation-dependent fitting of the R2 * and Δf measurements. The fitted 3D orientation vector maps and peak-to-peak amplitude of R2 * and Δf modulation exhibited close correspondence to primary eigenvector and anisotropy maps derived from diffusion MRI. The amplitude of B0 -orientation dependent R2 * modulation was significantly (P < 0.005) higher in the CST compared with TPF, while fractional anisotropies were comparable. CONCLUSION: The findings of this study demonstrate the potential of B0 -orientation dependent susceptibility-induced R2 * and Δf contrasts to probe tract-specific orientation and microstructure in white matter. Magn Reson Med 75:2455-2463, 2016. © 2016 Wiley Periodicals, Inc.
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Tronco Encefálico/diagnóstico por imagen , Procesamiento de Imagen Asistido por Computador/métodos , Imagen por Resonancia Magnética/métodos , Sustancia Blanca/diagnóstico por imagen , Adulto , Algoritmos , Anisotropía , Humanos , Tractos Piramidales/diagnóstico por imagenRESUMEN
CHCHD10-related diseases include mitochondrial DNA instability disorder, frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) clinical spectrum, late-onset spinal motor neuropathy (SMAJ), and Charcot-Marie-Tooth disease type 2 (CMT2). Here, we show that CHCHD10 resides with mitofilin, CHCHD3 and CHCHD6 within the "mitochondrial contact site and cristae organizing system" (MICOS) complex. CHCHD10 mutations lead to MICOS complex disassembly and loss of mitochondrial cristae with a decrease in nucleoid number and nucleoid disorganization. Repair of the mitochondrial genome after oxidative stress is impaired in CHCHD10 mutant fibroblasts and this likely explains the accumulation of deleted mtDNA molecules in patient muscle. CHCHD10 mutant fibroblasts are not defective in the delivery of mitochondria to lysosomes suggesting that impaired mitophagy does not contribute to mtDNA instability. Interestingly, the expression of CHCHD10 mutant alleles inhibits apoptosis by preventing cytochrome c release.
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Apoptosis/genética , Genoma Mitocondrial , Mitocondrias/genética , Proteínas Mitocondriales/genética , Alelos , Línea Celular , Citocromos c/metabolismo , Reparación del ADN/efectos de los fármacos , ADN Mitocondrial/análisis , ADN Mitocondrial/metabolismo , Células HeLa , Humanos , Peróxido de Hidrógeno/toxicidad , Lisosomas/metabolismo , Potencial de la Membrana Mitocondrial , Mitocondrias/metabolismo , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/patología , Proteínas Mitocondriales/metabolismo , Mutación , Estrés Oxidativo/efectos de los fármacos , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Maintaining mitochondrial dynamics and proper execution of mitophagy is crucial for sustaining cellular health. Defects in these processes have been linked to cardiovascular diseases and neurodegeneration. In a recent publication, we reported that the mitochondrial division dynamin protein DNM1L/Drp1 and the E3 ubiquitin ligase PARK2/Parkin work in a synergistic manner to maintain mitochondrial function and structural integrity in the mouse heart and brain.