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1.
Neurology ; 102(11): e209437, 2024 Jun 11.
Artículo en Inglés | MEDLINE | ID: mdl-38759141

RESUMEN

OBJECTIVES: To validate a recently published study in which skin biopsy was reported as a valuable alternative to brain biopsy in diagnosing CSF1R-related disorder (CSF1R-RD). METHODS: Blinded evaluation of skin samples was performed by independent reviewers using light and electron microscopy collected from a group of CSF1R variant carriers (n = 10) with various genotypes (mono and biallelic), different stages of the disease (asymptomatic and symptomatic), and exposed to different therapies (glucocorticoids, hematopoietic stem cell transplantation, and TREM2 agonist), and from a group of healthy controls (n = 5). RESULTS: Biopsies from patients with CSF1R-RD at various disease stages were indistinguishable from controls determined using light microscopy and electron microscopy. DISCUSSION: We found no distinctive axonal pathology in skin biopsies collected from CSF1R variant carriers at all stages of the disease. Our results are consistent with clinical and neurophysiologic features of the CSF1R-RD, in that peripheral nervous system involvement has not been reported. Studies aiming to discover new biomarkers are important, but the results must be validated with larger numbers of patients and healthy controls. Based on blinded light and electron microscopic studies of skin biopsies, there is no evidence that CSF1R-RD is associated with distinctive changes in cutaneous peripheral nerves. This suggests that skin biopsy is not useful in diagnosis of CSF1R-RD. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that skin biopsy does not distinguish those with CSF1R-RD, or carriers, from normal controls.


Asunto(s)
Biomarcadores , Piel , Humanos , Piel/patología , Biopsia , Femenino , Masculino , Adulto , Biomarcadores/líquido cefalorraquídeo , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Persona de Mediana Edad , Adulto Joven , Adolescente , Niño , Receptor de Factor Estimulante de Colonias de Macrófagos
2.
Stroke ; 53(12): 3696-3705, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36205142

RESUMEN

BACKGROUND: Cerebral small vessel disease (SVD) is common in older people and causes lacunar stroke and vascular cognitive impairment. Risk factors include old age, hypertension and variants in the genes COL4A1/COL4A2 encoding collagen alpha-1(IV) and alpha-2(IV), here termed collagen-IV, which are core components of the basement membrane. We tested the hypothesis that increased vascular collagen-IV associates with clinical hypertension and with SVD in older persons and with chronic hypertension in young and aged primates and genetically hypertensive rats. METHODS: We quantified vascular collagen-IV immunolabeling in small arteries in a cohort of older persons with minimal Alzheimer pathology (N=52; 21F/31M, age 82.8±6.95 years). We also studied archive tissue from young (age range 6.2-8.3 years) and older (17.0-22.7 years) primates (M mulatta) and compared chronically hypertensive animals (18 months aortic stenosis) with normotensives. We also compared genetically hypertensive and normotensive rats (aged 10-12 months). RESULTS: Collagen-IV immunolabeling in cerebral small arteries of older persons was negatively associated with radiological SVD severity (ρ: -0.427, P=0.005) but was not related to history of hypertension. General linear models confirmed the negative association of lower collagen-IV with radiological SVD (P<0.017), including age as a covariate and either clinical hypertension (P<0.030) or neuropathological SVD diagnosis (P<0.022) as fixed factors. Reduced vascular collagen-IV was accompanied by accumulation of fibrillar collagens (types I and III) as indicated by immunogold electron microscopy. In young and aged primates, brain collagen-IV was elevated in older normotensive relative to young normotensive animals (P=0.029) but was not associated with hypertension. Genetically hypertensive rats did not differ from normotensive rats in terms of arterial collagen-IV. CONCLUSIONS: Our cross-species data provide novel insight into sporadic SVD pathogenesis, supporting insufficient (rather than excessive) arterial collagen-IV in SVD, accompanied by matrix remodeling with elevated fibrillar collagen deposition. They also indicate that hypertension, a major risk factor for SVD, does not act by causing accumulation of brain vascular collagen-IV.


Asunto(s)
Enfermedades de los Pequeños Vasos Cerebrales , Hipertensión , Accidente Vascular Cerebral Lacunar , Animales , Ratas , Enfermedades de los Pequeños Vasos Cerebrales/complicaciones , Accidente Vascular Cerebral Lacunar/complicaciones , Hipertensión/complicaciones , Encéfalo/patología , Presión Sanguínea , Colágeno Tipo IV/genética
3.
Alzheimers Dement ; 2020 Oct 08.
Artículo en Inglés | MEDLINE | ID: mdl-33090691

RESUMEN

INTRODUCTION: The cytoprotective PTEN-induced kinase 1 (PINK1)-parkin RBR E3 ubiquitin protein ligase (PRKN) pathway selectively labels damaged mitochondria with phosphorylated ubiquitin (pS65-Ub) for their autophagic removal (mitophagy). Because dysfunctions of mitochondria and degradation pathways are early features of Alzheimer's disease (AD), mitophagy impairments may contribute to the pathogenesis. METHODS: Morphology, levels, and distribution of the mitophagy tag pS65-Ub were evaluated by biochemical analyses combined with tissue and single cell imaging in AD autopsy brain and in transgenic mouse models. RESULTS: Analyses revealed significant increases of pS65-Ub levels in AD brain, which strongly correlated with granulovacuolar degeneration (GVD) and early phospho-tau deposits, but were independent of amyloid beta pathology. Single cell analyses revealed predominant co-localization of pS65-Ub with mitochondria, GVD bodies, and/or lysosomes depending on the brain region analyzed. DISCUSSION: Our study highlights mitophagy alterations in AD that are associated with early tau pathology, and suggests that distinct mitochondrial, autophagic, and/or lysosomal failure may contribute to the selective vulnerability in disease.

4.
Artículo en Inglés | MEDLINE | ID: mdl-34386806

RESUMEN

BACKGROUND: The majority of cases of frontotemporal lobar degeneration (FTLD) are characterized by focal cortical atrophy with an underlying tau or TDP-43 proteinopathy. A subset of FTLD cases, however, lack tau and TDP-43 immuno-reactivity, but have neuronal inclusions positive for ubiquitin, referred to as atypical FTLD (aFTLD-U). Studies have demonstrated that ubiquitin-positive inclusions in aFTLD-U are immuno-reactive for fused in sarcoma (FUS). As such, the current nosology for this entity is FTLD-FUS, which is thought to include not only aFTLD-U, but also neuronal intermediate filament inclusion disease (NIFID) and basophilic inclusion body disease. OBJECTIVE: To compare pathological features of cases of aFTLD-U and NIFID. METHODS: We reviewed the neuropathology of 15 patients (10 males and 5 females; average age at death 54 years (range 41-69 years)) with an antemortem clinical diagnosis of a frontotemporal dementia and pathological diagnosis of aFTLD-U (n=8) or NIFID (n=7). Sections were processed for immunohistochemistry and immunoelectron microscopy with FUS, TDP-43, and α-internexin (αINX) antibodies. RESULTS: Eight cases had pathologic features consistent with FTLD-FUS, with severe striatal atrophy (7/8 cases), as well as FUS-positive neuronal cytoplasmic and vermiform intranuclear inclusions, but no αINX immuno-reactivity. Five cases had features consistent with NIFID, with neuronal inclusions positive for both FUS and αINX. Striatal atrophy was present in only 2 of the NIFID cases. Two cases had αINX-positive neuronal inclusions consistent with NIFID, but both lacked striatal atrophy and FUS immunoreactivity. Surprisingly, one of these two NIFID cases had lesions immunoreactive for TDP-43. DISCUSSION: While FUS pathology remains a prominent feature of aFTLD-U, there is pathologic heterogeneity, including rare cases of NIFID with TDP-43- rather than FUS-positive inclusions.

5.
Hum Mol Genet ; 28(19): 3255-3269, 2019 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-31261380

RESUMEN

Understanding the biological functions of tau variants can illuminate differential etiologies of Alzheimer's disease (AD) and primary tauopathies. Though the end-stage neuropathological attributes of AD and primary tauopathies are similar, the etiology and behavioral outcomes of these diseases follow unique and divergent trajectories. To study the divergent physiological properties of tau variants on a uniform immunogenetic background, we created somatic transgenesis CNS models of tauopathy utilizing neonatal delivery of adeno-associated viruses expressing wild-type (WT) or mutant tau in non-transgenic mice. We selected four different tau variants-WT tau associated with AD, P301L mutant tau associated with frontotemporal dementia (FTD), S320F mutant tau associated with Pick's disease and a combinatorial approach using P301L/S320F mutant tau. CNS-targeted expression of WT and P301L mutant tau results in robust tau hyperphosphorylation without tangle pathology, gradually developing age-progressive memory deficits. In contrast, the S320F variant, especially in combination with P301L, produces an AD-type tangle pathology, focal neuroinflammation and memory impairment on an accelerated time scale. Using the doubly mutated P301L/S320F tau variant, we demonstrate that combining different mutations can have an additive effect on neuropathologies and associated co-morbidities, possibly hinting at involvement of unique functional pathways. Importantly, we also show that overexpression of wild-type tau as well as an FTD-associated tau variant can lead to cognitive deficits even in the absence of tangles. Together, our data highlights the synergistic neuropathologies and associated cognitive and synaptic alterations of the combinatorial tau variant leading to a robust model of tauopathy.


Asunto(s)
Sistema Nervioso Central/metabolismo , Mutación , Tauopatías/genética , Proteínas tau/genética , Proteínas tau/metabolismo , Animales , Conducta Animal , Modelos Animales de Enfermedad , Femenino , Demencia Frontotemporal/genética , Demencia Frontotemporal/metabolismo , Demencia Frontotemporal/psicología , Humanos , Masculino , Ratones , Ratones Transgénicos , Fosforilación , Enfermedad de Pick/genética , Enfermedad de Pick/metabolismo , Enfermedad de Pick/psicología , Tauopatías/metabolismo , Tauopatías/psicología
6.
J Neuropathol Exp Neurol ; 78(5): 460-466, 2019 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-30990878

RESUMEN

Pathogenic hemizygous variants in the SH2D1A gene cause X-linked lymphoproliferative (XLP) syndrome, a rare primary immunodeficiency usually associated with fatal Epstein-Barr virus infection. Disease onset is typically in early childhood, and the average life expectancy of affected males is ∼11 years. We describe clinical, radiographic, neuropathologic, and genetic features of a 49-year-old man presenting with central nervous system vasculitis that was reminiscent of adult primary angiitis but which was unresponsive to treatment. The patient had 2 brothers; 1 died of aplastic anemia at age 13 and another died of diffuse large B-cell lymphoma in his sixties. Exome sequencing of the patient and his older brother identified a novel hemizygous variant in SH2D1A (c.35G>T, p.Ser12Ile), which encodes the signaling lymphocyte activation molecule (SLAM)-associated protein (SAP). Molecular modeling and functional analysis showed that this variant had decreased protein stability, similar to other pathogenic missense variants in SH2D1A. The family described in this report highlights the broadly heterogeneous clinical presentations of XLP and the accompanying diagnostic challenges in individuals presenting in adulthood. In addition, this report raises the possibility of a biphasic distribution of XLP cases, some of which may be mistaken for age-related malignancies and autoimmune conditions.


Asunto(s)
Demencia por Múltiples Infartos/diagnóstico por imagen , Demencia por Múltiples Infartos/genética , Trastornos Linfoproliferativos/diagnóstico por imagen , Trastornos Linfoproliferativos/genética , Proteína Asociada a la Molécula de Señalización de la Activación Linfocitaria/genética , Secuencia de Aminoácidos , Diagnóstico Diferencial , Humanos , Masculino , Persona de Mediana Edad , Linaje , Estructura Secundaria de Proteína , Proteína Asociada a la Molécula de Señalización de la Activación Linfocitaria/química
7.
J Exp Med ; 216(3): 539-555, 2019 03 04.
Artículo en Inglés | MEDLINE | ID: mdl-30770411

RESUMEN

It has been challenging to produce ex vivo models of the inclusion pathologies that are hallmark pathologies of many neurodegenerative diseases. Using three-dimensional mouse brain slice cultures (BSCs), we have developed a paradigm that rapidly and robustly recapitulates mature neurofibrillary inclusion and Lewy body formation found in Alzheimer's and Parkinson's disease, respectively. This was achieved by transducing the BSCs with recombinant adeno-associated viruses (rAAVs) that express α-synuclein or variants of tau. Notably, the tauopathy BSC model enables screening of small molecule therapeutics and tracking of neurodegeneration. More generally, the rAAV BSC "toolkit" enables efficient transduction and transgene expression from neurons, microglia, astrocytes, and oligodendrocytes, alone or in combination, with transgene expression lasting for many months. These rAAV-based BSC models provide a cost-effective and facile alternative to in vivo studies, and in the future can become a widely adopted methodology to explore physiological and pathological mechanisms related to brain function and dysfunction.


Asunto(s)
Enfermedad de Alzheimer/patología , Encéfalo/patología , Dependovirus/genética , Enfermedad de Parkinson/patología , Enfermedad de Alzheimer/virología , Animales , Encéfalo/metabolismo , Encéfalo/virología , Evaluación Preclínica de Medicamentos/métodos , Expresión Génica , Humanos , Ratones Endogámicos C3H , Ratones Transgénicos , Microorganismos Modificados Genéticamente , Mutación , Neuronas/patología , Técnicas de Cultivo de Órganos , Enfermedad de Parkinson/virología , Transducción Genética , Transgenes , alfa-Sinucleína/genética , Proteínas tau/genética
8.
Science ; 363(6428)2019 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-30765536

RESUMEN

How hexanucleotide GGGGCC (G4C2) repeat expansions in C9orf72 cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is not understood. We developed a mouse model engineered to express poly(PR), a proline-arginine (PR) dipeptide repeat protein synthesized from expanded G4C2 repeats. The expression of green fluorescent protein-conjugated (PR)50 (a 50-repeat PR protein) throughout the mouse brain yielded progressive brain atrophy, neuron loss, loss of poly(PR)-positive cells, and gliosis, culminating in motor and memory impairments. We found that poly(PR) bound DNA, localized to heterochromatin, and caused heterochromatin protein 1α (HP1α) liquid-phase disruptions, decreases in HP1α expression, abnormal histone methylation, and nuclear lamina invaginations. These aberrations of histone methylation, lamins, and HP1α, which regulate heterochromatin structure and gene expression, were accompanied by repetitive element expression and double-stranded RNA accumulation. Thus, we uncovered mechanisms by which poly(PR) may contribute to the pathogenesis of C9orf72-associated FTD and ALS.


Asunto(s)
Esclerosis Amiotrófica Lateral/metabolismo , Proteína C9orf72/metabolismo , Dipéptidos/metabolismo , Heterocromatina/patología , ARN Bicatenario/metabolismo , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/patología , Animales , Encéfalo/metabolismo , Proteína C9orf72/genética , Homólogo de la Proteína Chromobox 5 , Proteínas Cromosómicas no Histona/metabolismo , Dipéptidos/genética , Modelos Animales de Enfermedad , Proteínas Fluorescentes Verdes , Células HEK293 , Humanos , Ratones , Ratones Endogámicos C57BL , Lámina Nuclear/patología , Secuencias Repetitivas de Ácidos Nucleicos
9.
Cells ; 7(12)2018 Dec 16.
Artículo en Inglés | MEDLINE | ID: mdl-30558352

RESUMEN

Concentration of extracellular vesicles (EVs) from biological fluids in a scalable and reproducible manner represents a major challenge. This study reports the use of tangential flow filtration (TFF) for the highly efficient isolation of EVs from large volumes of samples. When compared to ultracentrifugation (UC), which is the most widely used method to concentrate EVs, TFF is a more efficient, scalable, and gentler method. Comparative assessment of TFF and UC of conditioned cell culture media revealed that the former concentrates EVs of comparable physicochemical characteristics, but with higher yield, less single macromolecules and aggregates (<15 nm in size), and improved batch-to-batch consistency in half the processing time (1 h). The TFF protocol was then successfully implemented on fluids derived from patient lipoaspirate. EVs from adipose tissue are of high clinical relevance, as they are expected to mirror the regenerative properties of the parent cells.

10.
Autophagy ; 14(8): 1404-1418, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29947276

RESUMEN

Although exact causes of Parkinson disease (PD) remain enigmatic, mitochondrial dysfunction is increasingly appreciated as a key determinant of dopaminergic neuron susceptibility in both familial and sporadic PD. Two genes associated with recessive, early-onset PD encode the ubiquitin (Ub) kinase PINK1 and the E3 Ub ligase PRKN/PARK2/Parkin, which together orchestrate a protective mitochondrial quality control (mitoQC) pathway. Upon stress, both enzymes cooperatively identify and decorate damaged mitochondria with phosphorylated poly-Ub (p-S65-Ub) chains. This specific label is subsequently recognized by autophagy receptors that further facilitate mitochondrial degradation in lysosomes (mitophagy). Here, we analyzed human post-mortem brain specimens and identified distinct pools of p-S65-Ub-positive structures that partially colocalized with markers of mitochondria, autophagy, lysosomes and/or granulovacuolar degeneration bodies. We further quantified levels and distribution of the 'mitophagy tag' in 2 large cohorts of brain samples from normal aging and Lewy body disease (LBD) cases using unbiased digital pathology. Somatic p-S65-Ub structures independently increased with age and disease in distinct brain regions and enhanced levels in LBD brain were age- and Braak tangle stage-dependent. Additionally, we observed significant correlations of p-S65-Ub with LBs and neurofibrillary tangle levels in disease. The degree of co-existing p-S65-Ub signals and pathological PD hallmarks increased in the pre-mature stage, but decreased in the late stage of LB or tangle aggregation. Altogether, our study provides further evidence for a potential pathogenic overlap among different forms of PD and suggests that p-S65-Ub can serve as a biomarker for mitochondrial damage in aging and disease. ABBREVIATIONS: BLBD: brainstem predominant Lewy body disease; CCCP: carbonyl cyanide m-chlorophenyl hydrazone; DLB: dementia with Lewy bodies; DLBD: diffuse neocortical Lewy body disease; EOPD: early-onset Parkinson disease; GVB: granulovacuolar degeneration body; LB: Lewy body; LBD: Lewy body disease; mitoQC: mitochondrial quality control; nbM: nucleus basalis of Meynert; PD: Parkinson disease; PDD: Parkinson disease with dementia; p-S65-Ub: PINK1-phosphorylated serine 65 ubiquitin; SN: substantia nigra; TLBD: transitional Lewy body disease; Ub: ubiquitin.


Asunto(s)
Envejecimiento/metabolismo , Biomarcadores/metabolismo , Enfermedad por Cuerpos de Lewy/metabolismo , Enfermedad por Cuerpos de Lewy/patología , Mitofagia , Ubiquitina/metabolismo , Anciano , Anciano de 80 o más Años , Encéfalo/metabolismo , Encéfalo/ultraestructura , Estudios de Cohortes , Femenino , Células HeLa , Humanos , Masculino , Persona de Mediana Edad , Mutación/genética , Fosforilación , Fosfoserina/metabolismo , Unión Proteica , alfa-Sinucleína/metabolismo , Proteínas tau/metabolismo
11.
J Neuropathol Exp Neurol ; 76(8): 676-682, 2017 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-28789478

RESUMEN

Perry syndrome is a rare atypical parkinsonism with depression, apathy, weight loss, and central hypoventilation caused by mutations in dynactin p150glued (DCTN1). A rare distal hereditary motor neuropathy, HMN7B, also has mutations in DCTN1. Perry syndrome has TAR DNA-binding protein of 43 kDa (TDP-43) inclusions as a defining feature. Other TDP-43 proteinopathies include amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with and without motor neuron disease (FTLD-MND). TDP-43 forms aggregates in neuronal cytoplasmic inclusions (NCIs), neuronal intranuclear inclusions, dystrophic neurites (DNs), as well as axonal spheroids, oligodendroglial cytoplasmic inclusions, and perivascular astrocytic inclusions (PVIs). We performed semiquantitative assessment of these lesions and presence of dynactin subunit p50 lesions in 3 cases of Perry syndrome and one of HMN7B. We compared them with 3 cases of FTLD-MND, 3 of ALS, and 3 of hippocampal sclerosis (HpScl). Perry syndrome had NCIs, DNs, and frequent PVIs and spheroids. Perry syndrome cases were similar, but different from ALS, FTLD-MND, and HpScl. TDP-43 pathology was not detected in HMN7B. Dynactin p50 inclusions were observed in both Perry syndrome and HMN7B, but not in the other conditions. These results suggest that Perry syndrome may be distinctive type of TDP-43 proteinopathy.


Asunto(s)
Tronco Encefálico/metabolismo , Proteínas de Unión al ADN/genética , Hipoventilación/genética , Hipoventilación/patología , Trastornos Parkinsonianos/genética , Trastornos Parkinsonianos/patología , Proteinopatías TDP-43/clasificación , Proteinopatías TDP-43/patología , Anciano , Anciano de 80 o más Años , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/patología , Tronco Encefálico/patología , Tronco Encefálico/ultraestructura , Proteínas de Unión al ADN/metabolismo , Depresión/genética , Depresión/patología , Complejo Dinactina/genética , Complejo Dinactina/metabolismo , Salud de la Familia , Femenino , Humanos , Masculino , Microscopía Inmunoelectrónica , Persona de Mediana Edad
12.
PLoS One ; 12(1): e0169291, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28076378

RESUMEN

One of the proteins most frequently found in neuropathological lesions is the ubiquitin binding protein p62 (sequestosome 1). Post-mortem analysis of p62 is a defining diagnostic marker in several neurodegenerative diseases including amyotrophic lateral sclerosis and inclusion body myositis. Since p62 functions in protein degradation pathways including autophagy, the build-up of p62-positive inclusions suggests defects in protein clearance. p62 was expressed unilaterally in the rat substantia nigra with an adeno-associated virus vector (AAV9) in order to study p62 neuropathology. Inclusions formed within neurons from several days to several weeks after gene transfer. By electron microscopy, the inclusions were found to contain packed 10 nm thick filaments, and mitochondria cristae structure was disrupted, resulting in the formation of empty spaces. In corollary cell culture transfections, p62 clearly impaired mitochondrial function. To probe for potential effects on macroautophagy, we co-expressed p62 with a double fluorescent tagged reporter for the autophagosome protein LC3 in the rat. p62 induced a dramatic and specific dissociation of the two tags. By 12 weeks, a rotational behavior phenotype manifested, consistent with a significant loss of dopaminergic neurons analyzed post-mortem. p62 overexpression resulted in a progressive and robust pathology model with neuronal inclusions and neurodegeneration. p62 gene transfer could be a novel methodological probe to disrupt mitochondrial function or autophagy in the brain and other tissues in vivo.


Asunto(s)
Cuerpos de Inclusión/genética , Cuerpos de Inclusión/patología , Enfermedades Neurodegenerativas/genética , Proteína Sequestosoma-1/genética , Sustancia Negra/metabolismo , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/patología , Animales , Modelos Animales de Enfermedad , Femenino , Células HEK293 , Humanos , Miositis por Cuerpos de Inclusión/genética , Miositis por Cuerpos de Inclusión/patología , Enfermedades Neurodegenerativas/patología , Ratas , Ratas Sprague-Dawley , Ratas Transgénicas , Proteína Sequestosoma-1/fisiología
13.
Brain Pathol ; 27(5): 612-626, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-27529406

RESUMEN

Mutations in microtubule-associated protein tau gene (MAPT) cause frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). Here, we describe a patient with FTDP-17 and a novel missense mutation in exon 13 of MAPT, p.E372G. We compare clinicopathologic features of this patient to two previously unreported patients with another exon 13 mutation, p.G389R. The patient with the p.E372G mutation was a 40-year-old man with behavioral variant frontotemporal dementia (bvFTD), who subsequently developed agrammatic speech and parkinsonism. One of the FTDP-17 patients with p.G389R mutation presented at age 24 with agrammatic variant of primary progressive aphasia, and subsequently behavioral dysfunction. The other presented at age 53 with bvFTD, followed by agrammatic speech and corticobasal syndrome. Neuropathologic features of FTDP-17 due to p.E372G were similar to those of p.G389R, including tau-immunoreactive Pick body-like neuronal inclusions and swollen, tapering thread-like processes in white matter immunoreactive for 3-repeat and 4-repeat tau. Biochemical analysis of insoluble tau showed similar isoform compositions in p.E372G and p.G389R. Functional studies of the p.E372G mutation showed marked increase in tau filament formation and its reduced ability to promote microtubule assembly. Together these findings indicate that p.E372G is a pathogenic MAPT mutation that causes FTDP-17 similar to p.G389R.


Asunto(s)
Corteza Cerebral/patología , Demencia Frontotemporal/genética , Demencia Frontotemporal/patología , Proteínas tau/genética , Adulto , Corteza Cerebral/ultraestructura , Femenino , Humanos , Cuerpos de Inclusión , Masculino , Persona de Mediana Edad , Mutación Missense , Adulto Joven
14.
Nat Neurosci ; 19(5): 668-677, 2016 05.
Artículo en Inglés | MEDLINE | ID: mdl-26998601

RESUMEN

Neuronal inclusions of poly(GA), a protein unconventionally translated from G4C2 repeat expansions in C9ORF72, are abundant in patients with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) caused by this mutation. To investigate poly(GA) toxicity, we generated mice that exhibit poly(GA) pathology, neurodegeneration and behavioral abnormalities reminiscent of FTD and ALS. These phenotypes occurred in the absence of TDP-43 pathology and required poly(GA) aggregation. HR23 proteins involved in proteasomal degradation and proteins involved in nucleocytoplasmic transport were sequestered by poly(GA) in these mice. HR23A and HR23B similarly colocalized to poly(GA) inclusions in C9ORF72 expansion carriers. Sequestration was accompanied by an accumulation of ubiquitinated proteins and decreased xeroderma pigmentosum C (XPC) levels in mice, indicative of HR23A and HR23B dysfunction. Restoring HR23B levels attenuated poly(GA) aggregation and rescued poly(GA)-induced toxicity in neuronal cultures. These data demonstrate that sequestration and impairment of nuclear HR23 and nucleocytoplasmic transport proteins is an outcome of, and a contributor to, poly(GA) pathology.


Asunto(s)
Proteínas Portadoras/metabolismo , Proteínas de Unión al ADN/metabolismo , Factores de Intercambio de Guanina Nucleótido/metabolismo , Neuronas/patología , Proteínas/toxicidad , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/patología , Animales , Atrofia/patología , Conducta Animal , Encéfalo/metabolismo , Encéfalo/patología , Encéfalo/ultraestructura , Proteína C9orf72 , Demencia Frontotemporal/metabolismo , Demencia Frontotemporal/patología , Expresión Génica/genética , Humanos , Cuerpos de Inclusión/metabolismo , Cuerpos de Inclusión/ultraestructura , Ratones , Mutación , Degeneración Nerviosa/patología , Neuronas/metabolismo , Cultivo Primario de Células , Proteínas/genética , Proteínas/metabolismo , Proteínas Ubiquitinadas/metabolismo
15.
Neuron ; 88(4): 678-90, 2015 Nov 18.
Artículo en Inglés | MEDLINE | ID: mdl-26526393

RESUMEN

The mechanisms by which mutations in FUS and other RNA binding proteins cause ALS and FTD remain controversial. We propose a model in which low-complexity (LC) domains of FUS drive its physiologically reversible assembly into membrane-free, liquid droplet and hydrogel-like structures. ALS/FTD mutations in LC or non-LC domains induce further phase transition into poorly soluble fibrillar hydrogels distinct from conventional amyloids. These assemblies are necessary and sufficient for neurotoxicity in a C. elegans model of FUS-dependent neurodegeneration. They trap other ribonucleoprotein (RNP) granule components and disrupt RNP granule function. One consequence is impairment of new protein synthesis by cytoplasmic RNP granules in axon terminals, where RNP granules regulate local RNA metabolism and translation. Nuclear FUS granules may be similarly affected. Inhibiting formation of these fibrillar hydrogel assemblies mitigates neurotoxicity and suggests a potential therapeutic strategy that may also be applicable to ALS/FTD associated with mutations in other RNA binding proteins.


Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Proteínas de Caenorhabditis elegans/genética , Degeneración Lobar Frontotemporal/genética , Hidrogeles , Actividad Motora/genética , Transición de Fase , ARN Mensajero/metabolismo , Proteína FUS de Unión a ARN/genética , Animales , Caenorhabditis elegans , Gránulos Citoplasmáticos/metabolismo , Modelos Animales de Enfermedad , Longevidad , Mutación , Proteína FUS de Unión a ARN/química , Ribonucleoproteínas/metabolismo
16.
J Neuropathol Exp Neurol ; 74(11): 1042-52, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26426266

RESUMEN

Pick disease (PiD) is a frontotemporal lobar degeneration with distinctive neuronal inclusions (Pick bodies) that are enriched in 3-repeat (3R) tau. Although mostly sporadic, mutations in the tau gene (MAPT) have been reported. We screened 24 cases of neuropathologically confirmed PiD for MAPT mutations and found a novel mutation (c.1008G>C, p.Q336H) in 1 patient. Pathogenicity was confirmed on microtubule assembly and tau filament formation assays. The patient was compared with sporadic PiD and PiD associated with MAPT mutations from a review of the literature. The patient had behavioral changes at 55 years of age, followed by reduced verbal fluency, parkinsonism, and death at 63 years of age. His mother and maternal uncle had similar symptoms. Recombinant tau with p.Q336H mutation formed filaments faster than wild-type tau, especially with 3R tau. It also promoted more microtubule assembly than wild-type tau. We conclude that mutations in MAPT, including p.Q336H, can be associated with clinical, pathologic, and biochemical features that are similar to those in sporadic PiD. The pathomechanism of p.Q336H, and another previously reported variant at the same codon (p.Q336R), seems to be unique to MAPT mutations in that they not only predispose to abnormal tau filament formation but also facilitate microtubule assembly in a 3R tau-dependent manner.


Asunto(s)
Exones/genética , Ácido Glutámico/genética , Histidina/genética , Mutación/genética , Enfermedad de Pick/genética , Proteínas tau/genética , Encéfalo/metabolismo , Encéfalo/patología , Análisis Mutacional de ADN , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Pick/patología , Ubiquitina/metabolismo , alfa-Sinucleína/metabolismo
17.
Hum Mol Genet ; 24(21): 6198-212, 2015 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-26276810

RESUMEN

Aberrant tau protein accumulation drives neurofibrillary tangle (NFT) formation in several neurodegenerative diseases. Currently, efforts to elucidate pathogenic mechanisms and assess the efficacy of therapeutic targets are limited by constraints of existing models of tauopathy. In order to generate a more versatile mouse model of tauopathy, somatic brain transgenesis was utilized to deliver adeno-associated virus serotype 1 (AAV1) encoding human mutant P301L-tau compared with GFP control. At 6 months of age, we observed widespread human tau expression with concomitant accumulation of hyperphosphorylated and abnormally folded proteinase K resistant tau. However, no overt neuronal loss was observed, though significant abnormalities were noted in the postsynaptic scaffolding protein PSD95. Neurofibrillary pathology was also detected with Gallyas silver stain and Thioflavin-S, and electron microscopy revealed the deposition of closely packed filaments. In addition to classic markers of tauopathy, significant neuroinflammation and extensive gliosis were detected in AAV1-Tau(P301L) mice. This model also recapitulates the behavioral phenotype characteristic of mouse models of tauopathy, including abnormalities in exploration, anxiety, and learning and memory. These findings indicate that biochemical and neuropathological hallmarks of tauopathies are accurately conserved and are independent of cell death in this novel AAV-based model of tauopathy, which offers exceptional versatility and speed in comparison with existing transgenic models. Therefore, we anticipate this approach will facilitate the identification and validation of genetic modifiers of disease, as well as accelerate preclinical assessment of potential therapeutic targets.


Asunto(s)
Encéfalo/ultraestructura , Modelos Animales de Enfermedad , Tauopatías , Proteínas tau/metabolismo , Animales , Conducta Animal , Muerte Celular , Humanos , Ratones , Ratones Transgénicos , Ovillos Neurofibrilares/diagnóstico por imagen , Neuronas/patología , Tauopatías/genética , Tauopatías/metabolismo , Tauopatías/patología , Ultrasonografía , Proteínas tau/genética
18.
Acta Neuropathol ; 130(1): 93-105, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25962793

RESUMEN

Multiple system atrophy (MSA) is a sporadic neurodegenerative disease clinically characterized by cerebellar signs, parkinsonism, and autonomic dysfunction. Pathologically, MSA is an α-synucleinopathy affecting striatonigral and olivopontocerebellar systems, while neocortical and limbic involvement is usually minimal. In this study, we describe four patients with atypical MSA with clinical features consistent with frontotemporal dementia (FTD), including two with corticobasal syndrome, one with progressive non-fluent aphasia, and one with behavioral variant FTD. None had autonomic dysfunction. All had frontotemporal atrophy and severe limbic α-synuclein neuronal pathology. The neuronal inclusions were heterogeneous, but included Pick body-like inclusions. The latter were strongly associated with neuronal loss in the hippocampus and amygdala. Unlike typical Pick bodies, the neuronal inclusions were positive on Gallyas silver stain and negative on tau immunohistochemistry. In comparison to 34 typical MSA cases, atypical MSA had significantly more neuronal inclusions in anteromedial temporal lobe and limbic structures. While uncommon, our findings suggest that MSA may present clinically and pathologically as a frontotemporal lobar degeneration (FTLD). We suggest that this may represent a novel subtype of FTLD associated with α-synuclein (FTLD-synuclein).


Asunto(s)
Encéfalo/patología , Degeneración Lobar Frontotemporal/patología , Atrofia de Múltiples Sistemas/patología , alfa-Sinucleína/metabolismo , Anciano , Anciano de 80 o más Años , Encéfalo/metabolismo , Femenino , Degeneración Lobar Frontotemporal/genética , Degeneración Lobar Frontotemporal/fisiopatología , Humanos , Atrofia de Múltiples Sistemas/genética , Atrofia de Múltiples Sistemas/fisiopatología , alfa-Sinucleína/genética , Proteínas tau/metabolismo
19.
Acta Neuropathol ; 130(2): 199-214, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25900293

RESUMEN

Globular glial tauopathies (GGTs) are 4-repeat tauopathies neuropathologically characterized by tau-positive, globular glial inclusions, including both globular oligodendroglial inclusions and globular astrocytic inclusions. No mutations have been found in 25 of the 30 GGT cases reported in the literature who have been screened for mutations in microtubule associated protein tau (MAPT). In this report, six patients with GGT (four with subtype III and two with subtype I) were screened for MAPT mutations. They included 4 men and 2 women with a mean age at death of 73 years (55-83 years) and mean age at symptomatic onset of 66 years (50-77 years). Disease duration ranged from 5 to 14 years. All were homozygous for the MAPT H1 haplotype. Three patients had a positive family history of dementia, and a novel MAPT mutation (c.951G>C, p.K317N) was identified in one of them, a patient with subtype III. Recombinant tau protein bearing the lysine-to-asparagine substitution at amino acid residue 317 was used to assess functional significance of the variant on microtubule assembly and tau filament formation. Recombinant p.K317N tau had reduced ability to promote tubulin polymerization. Recombinant 3R and 4R tau bearing the p.K317N mutation showed decreased 3R tau and increased 4R tau filament assembly. These results strongly suggest that the p.K317N variant is pathogenic. Sequencing of MAPT should be considered in patients with GGT and a family history of dementia or movement disorder. Since several individuals in our series had a positive family history but no MAPT mutation, genetic factors other than MAPT may play a role in disease pathogenesis.


Asunto(s)
Mutación , Tauopatías/genética , Proteínas tau/genética , Anciano , Anciano de 80 o más Años , Encéfalo/metabolismo , Encéfalo/patología , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Microscopía Electroquímica de Rastreo , Microtúbulos/metabolismo , Persona de Mediana Edad , Linaje , Polimerizacion , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Tauopatías/metabolismo , Tauopatías/patología , Tubulina (Proteína)/metabolismo , Proteínas tau/aislamiento & purificación , Proteínas tau/metabolismo
20.
Acta Neuropathol ; 130(1): 145-57, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25917047

RESUMEN

Amyotrophic lateral sclerosis (ALS) is a degenerative disorder affecting upper and lower motor neurons, but it is increasingly recognized to affect other systems, with cognitive impairment resembling frontotemporal dementia (FTD) in some patients. We report clinical and pathologic findings of a family with ALS due to a truncating mutation, p.Gly141X, in copper/zinc superoxide dismutase (SOD1). The proband presented clinically with FTD and later showed progressive motor neuron disease, while all other family members had early-onset and rapidly progressive ALS without significant cognitive deficits. Pathologic examination of both the proband and her daughter revealed degeneration of corticospinal tracts and motor neurons in brain and spinal cord compatible with ALS. On the other hand, the proband also had neocortical and limbic system degeneration with pleomorphic neuronal cytoplasmic inclusions. Extramotor pathology in her daughter was relatively restricted to the hypothalamus and extrapyramidal system, but not the neocortex. The inclusions in the proband and her daughter were immunoreactive for SOD1, but negative for TAR DNA-binding protein of 43 kDa (TDP-43). In the proband, a number of the neocortical inclusions were immunopositive for α-internexin, initially suggesting a diagnosis of atypical FTLD, but there was no evidence of fused in sarcoma (FUS) immunoreactivity, which is often detected in atypical FTLD. Analogous to atypical FTLD, neuronal inclusions had variable co-localization of SOD1 and α-internexin. The current classification of FTLD is based on the major constituent protein: FTLD-tau, FTLD-TDP-43, and FTLD-FUS. The proband in this family indicates that SOD1, while rare, can also be the substrate of FTLD, in addition to the more common presentation of ALS. The explanation for clinical and pathologic heterogeneity of SOD1 mutations, including the p.Gly141X mutation, remains unresolved.


Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Encéfalo/patología , Degeneración Lobar Frontotemporal/genética , Mutación , Superóxido Dismutasa/genética , Adulto , Esclerosis Amiotrófica Lateral/patología , Esclerosis Amiotrófica Lateral/fisiopatología , Encéfalo/metabolismo , Familia , Resultado Fatal , Femenino , Degeneración Lobar Frontotemporal/patología , Degeneración Lobar Frontotemporal/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Linaje , Superóxido Dismutasa-1
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