RESUMO
Inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia (IBMPFD) is a dominantly inherited degenerative disorder caused by mutations in the valosin-containing protein (VCP7) gene. VCP (p97 in mouse, TER94 in Drosophila melanogaster, and CDC48 in Saccharomyces cerevisiae) is a highly conserved AAA(+) (ATPases associated with multiple cellular activities) ATPase that regulates a wide array of cellular processes. The mechanism of IBMPFD pathogenesis is unknown. To elucidate the pathogenic mechanism, we developed and characterized a Drosophila model of IBMPFD (mutant-VCP-related degeneration). Based on genetic screening of this model, we identified three RNA-binding proteins that dominantly suppressed degeneration; one of these was TBPH, the Drosophila homolog of TAR (trans-activating response region) DNA-binding protein 43 (TDP-43). Here we demonstrate that VCP and TDP-43 interact genetically and that disease-causing mutations in VCP lead to redistribution of TDP-43 to the cytoplasm in vitro and in vivo, replicating the major pathology observed in IBMPFD and other TDP-43 proteinopathies. We also demonstrate that TDP-43 redistribution from the nucleus to the cytoplasm is sufficient to induce cytotoxicity. Furthermore, we determined that a pathogenic mutation in TDP-43 promotes redistribution to the cytoplasm and enhances the genetic interaction with VCP. Together, our results show that degeneration associated with VCP mutations is mediated in part by toxic gain of function of TDP-43 in the cytoplasm. We suggest that these findings are likely relevant to the pathogenic mechanism of a broad array of TDP-43 proteinopathies, including frontotemporal lobar degeneration and amyotrophic lateral sclerosis.
Assuntos
Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas de Drosophila/genética , Demência Frontotemporal/genética , Mutação/genética , Osteíte Deformante/genética , Aminopeptidases/metabolismo , Animais , Animais Geneticamente Modificados , Sítios de Ligação/genética , Linhagem Celular Transformada , Sistema Nervoso Central/metabolismo , Citoplasma/genética , Citoplasma/metabolismo , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Drosophila , Proteínas de Drosophila/metabolismo , Demência Frontotemporal/complicações , Demência Frontotemporal/patologia , Regulação da Expressão Gênica/genética , Glicoproteínas/metabolismo , Humanos , Indóis , Modelos Biológicos , Osteíte Deformante/complicações , Regiões Promotoras Genéticas/genética , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Saccharomyces cerevisiae/genética , Transfecção/métodos , Proteína com ValosinaRESUMO
A wide variety of neurodegenerative diseases are characterized by the accumulation of intracellular or extracellular protein aggregates. More recently, the genetic identification of mutations in familial counterparts to the sporadic disorders, leading to the development of in vitro and in vivo model systems, has provided insights into disease pathogenesis. The effect of many of these mutations is the abnormal processing of misfolded proteins that overwhelms the quality-control systems of the cell, resulting in the deposition of protein aggregates in the nucleus, cytosol and/or extracellular space. Further understanding of mechanisms regulating protein processing and aggregation, as well as of the toxic effects of misfolded neurodegenerative disease proteins, will facilitate development of rationally designed therapies to treat and prevent these disorders.
Assuntos
Corpos de Lewy/genética , Modelos Biológicos , Proteínas do Tecido Nervoso/genética , Doenças Neurodegenerativas/história , Doenças Neurodegenerativas/terapia , Príons/genética , Dobramento de Proteína , Doença de Alzheimer/genética , Doença de Alzheimer/história , Doença de Alzheimer/terapia , Peptídeos beta-Amiloides/metabolismo , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/história , Esclerose Lateral Amiotrófica/terapia , Síndrome de Creutzfeldt-Jakob/genética , Síndrome de Creutzfeldt-Jakob/história , Síndrome de Creutzfeldt-Jakob/terapia , História do Século XX , História do Século XXI , Humanos , Corpos de Lewy/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Doenças Neurodegenerativas/genética , Peptídeos/metabolismo , Príons/metabolismo , Superóxido Dismutase/metabolismo , SinucleínasRESUMO
The discovery of SNCA mutations pathogenic for autosomal-dominant Lewy body Parkinson's disease (PD) in 1997 heralded a revolution in understanding the molecular and genetic basis of PD. Indeed, it now is clear that Lewy body PD is one of many neurodegenerative parkinsonian disorders that result from nigrostriatal degeneration caused by diverse mechanisms. However, to capitalize on these new insights and facilitate efforts to improve the diagnosis and therapy of neurodegenerative movement disorders, it is timely to define a nosology for these diseases that is based on their genetic and molecular underpinnings, as proposed here.
Assuntos
Degeneração Neural/genética , Proteínas do Tecido Nervoso/genética , Doença de Parkinson/classificação , Doença de Parkinson/genética , Animais , Predisposição Genética para Doença/genética , Humanos , Mutação/genética , Substância Negra/metabolismo , Substância Negra/patologia , Substância Negra/fisiopatologia , Sinucleínas , Terminologia como Assunto , alfa-SinucleínaRESUMO
Over the past decade, it has become clear that there is a significant overlap in the clinical spectrum of frontotemporal lobar degeneration and amyotrophic lateral sclerosis (ALS). The identification of TDP-43 as the major disease protein in the pathology of both frontotemporal lobar degeneration with ubiquitin inclusions and ALS provides the first molecular link for these diseases. Pathological TDP-43 is abnormally phosphorylated, ubiquitinated, and cleaved to generate carboxy-terminal fragments in affected brain regions. The normal nuclear expression of TDP-43 is also reduced leading to the hypothesis that sequestration of TDP-43 in pathological inclusions contributes to disease pathogenesis. Thus, TDP-43 is the newest member of the growing list of neurodegenerative proteinopathies, but unique in that it lacks features of brain amyloidosis.
Assuntos
Esclerose Lateral Amiotrófica/metabolismo , Proteínas de Ligação a DNA/metabolismo , Demência/metabolismo , Esclerose Lateral Amiotrófica/patologia , Demência/patologia , Humanos , Ubiquitina/metabolismoRESUMO
Accumulation of hyperphosphorylated, ubiquitinated and N-terminally truncated TAR DNA-binding protein (TDP-43) is the pathological hallmark lesion in most familial and sporadic forms of FTLD-U and ALS, which can be subsumed as TDP-43 proteinopathies. In order to get more insight into the role of abnormal phosphorylation in the disease process, the identification of specific phosphorylation sites and the generation of phosphorylation-specific antibodies are mandatory. Here, we developed and characterized novel rat monoclonal antibodies (1D3 and 7A9) raised against phosphorylated S409/410 of TDP-43. These antibodies were used to study the presence of S409/410 phosphorylation by immunohistochemistry and biochemical analysis in a large series of 64 FTLD-U cases with or without motor neuron disease including familial cases with mutations in progranulin (n = 5), valosin-containing protein (n = 4) and linkage to chromosome 9p (n = 4), 18 ALS cases as well as other neurodegenerative diseases with concomitant TDP-43 pathology (n = 5). Our data demonstrate that phosphorylation of S409/410 of TDP-43 is a highly consistent feature in pathologic inclusions in the whole spectrum of sporadic and familial forms of TDP-43 proteinopathies. Physiological nuclear TDP-43 was not detectable with these mAbs by immunohistochemistry and by immunoblot analyses. While the accumulation of phosphorylated C-terminal fragments was a robust finding in the cortical brain regions of FTLD-U and ALS, usually being much more abundant than the phosphorylated full-length TDP-43 band, spinal cord samples revealed a predominance of full-length TDP-43 over C-terminal fragments. This argues for a distinct TDP-43 species composition in inclusions in cortical versus spinal cord cells. Overall, these mAbs are powerful tools for the highly specific detection of disease-associated abnormal TDP-43 species and will be extremely useful for the neuropathological routine diagnostics of TDP-43 proteinopathies and for the investigation of emerging cellular and animal models for TDP-43 proteinopathies.
Assuntos
Esclerose Lateral Amiotrófica/metabolismo , Encéfalo/metabolismo , Proteínas de Ligação a DNA/metabolismo , Demência/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Esclerose Lateral Amiotrófica/complicações , Esclerose Lateral Amiotrófica/patologia , Animais , Anticorpos Monoclonais/biossíntese , Anticorpos Monoclonais/imunologia , Encéfalo/patologia , Proteínas de Ligação a DNA/imunologia , Demência/complicações , Demência/patologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Immunoblotting , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Doença dos Neurônios Motores/complicações , Doença dos Neurônios Motores/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Fosforilação , Ratos , Medula Espinal/metabolismoRESUMO
ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) is required for the production of ß-amyloid (Aß) peptides and is considered a potential treatment target for Alzheimer's disease (AD). To support Japan's participation in the global clinical development program, we characterized the safety, pharmacokinetics (PKs), and pharmacodynamics of the BACE1 inhibitor verubecestat (MK-8931) in 24 healthy Japanese adults in a two-part, single-center, randomized, placebo-controlled phase I trial (protocol MK-8931-007) and compared the results with historical data from non-Japanese subjects. Both single (20, 100, and 450 mg) and multiple (80 and 150 mg once daily for 14 days) doses of verubecestat were well tolerated. Verubecestat's PK profile was similar in Japanese and non-Japanese subjects. Verubecestat also reduced mean cerebrospinal fluid concentrations of the Aß proteins Aß40, Aß42, and soluble ß fragment of amyloid precursor protein; the level of reduction was comparable between Japanese and non-Japanese subjects. These results support the continued global development of verubecestat as a potential disease-modifying agent for Japanese and non-Japanese subjects who are at risk for developing AD.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Óxidos S-Cíclicos , Tiadiazinas , Adulto , Doença de Alzheimer/etnologia , Peptídeos beta-Amiloides/sangue , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Precursor de Proteína beta-Amiloide/sangue , Precursor de Proteína beta-Amiloide/metabolismo , Óxidos S-Cíclicos/administração & dosagem , Óxidos S-Cíclicos/farmacocinética , Relação Dose-Resposta a Droga , Esquema de Medicação , Monitoramento de Medicamentos/métodos , Feminino , Voluntários Saudáveis , Humanos , Japão , Masculino , Tiadiazinas/administração & dosagem , Tiadiazinas/farmacocinéticaRESUMO
Pathologic TAR-DNA-binding protein 43 (TDP-43) is a disease protein in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis. We studied the presence, frequency, and distribution of TDP-43 pathology by immunohistochemistry and biochemistry in a series of clinically well-characterized tauopathy patient brains, including 182 Alzheimer disease (AD), 39 corticobasal degeneration, 77 progressive supranuclear palsy, and 12 Pick disease cases and investigated the clinical impact of concomitant TDP-43 pathology in these cases. TAR-DNA-binding protein 43 pathology was found in 25.8% of AD cases. It was restricted to the dentate gyrus and entorhinal cortex in approximately 75% of cases; approximately 25% showed more widespread TDP-43 pathology in frontal and temporal cortices, resembling the FTLD-U subtype associated with progranulin mutations. TAR-DNA-binding protein 43 pathology in AD was associated with significantly longer disease duration, but there was no association with the clinical presentation (148 cases diagnosed as AD and 34 cases diagnosed as frontotemporal lobar degeneration). Progressive supranuclear palsy and Pick disease cases showed no TDP-43 inclusions and no biochemical alterations of TDP-43. There was, however, a unique, predominantly glial TDP-43 pathology with staining of astrocytic plaque-like structures and coiled bodies in 15.4% of corticobasal degeneration cases; this was associated with biochemical TDP-43 changes similar to those in FTLD-U. These findings provide further insight into the burden and clinical significance of TDP-43 pathology in disorders other than FTLD-U and amyotrophic lateral sclerosis.
Assuntos
Doença de Alzheimer/patologia , Encéfalo/patologia , Proteínas de Ligação a DNA/metabolismo , Neurônios/patologia , Tauopatias/patologia , Idoso , Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Feminino , Humanos , Immunoblotting , Imuno-Histoquímica , Corpos de Inclusão/metabolismo , Corpos de Inclusão/patologia , Masculino , Neurônios/metabolismo , Tauopatias/metabolismoRESUMO
Inclusion body myopathy with Paget disease of the bone (PDB) and/or frontotemporal dementia (IBMPFD, OMIM 167320), is a progressive autosomal dominant disorder caused by mutations in the Valousin-containing protein (VCP, p97 or CDC48) gene. IBMPFD can be difficult to diagnose. We assembled data on a large set of families to illustrate the number and type of misdiagnoses that occurred. Clinical analysis of 49 affected individuals in nine families indicated that 42 (87%) of individuals had muscle disease. The majority were erroneously diagnosed with limb girdle muscular dystrophy (LGMD), facioscapular muscular dystrophy, peroneal muscular dystrophy, late adult onset distal myopathy, spinal muscular atrophy, scapuloperoneal muscular dystrophy, or amyotrophic lateral sclerosis (ALS) among others. Muscle biopsies showed rimmed vacuoles characteristic of an inclusion body myopathy in 7 of 18 patients (39%), however, inclusion body myopathy was correctly diagnosed among individuals in only families 5 and 15. Frontotemporal dementia (FTD) was diagnosed in 13 individuals (27%) at a mean age of 57 years (range 48.9-60.2 years); however, several individuals had been diagnosed with Alzheimer disease. Histopathological examination of brains of three affected individuals revealed a pattern of ubiquitin positive neuronal intranuclear inclusions and dystrophic neurites. These families expand the clinical phenotype in IBMPFD, a complex disorder caused by mutations in VCP. The presence of PDB in 28 (57%) individuals suggests that measuring serum alkaline phosphatase (ALP) activity may be a useful screen for IBMPFD in patients with myopathy.
Assuntos
Adenosina Trifosfatases/genética , Proteínas de Ciclo Celular/genética , Demência/complicações , Demência/genética , Família , Doenças Musculares/complicações , Doenças Musculares/genética , Osteíte Deformante/complicações , Osteíte Deformante/genética , Adulto , Estudos Transversais , Feminino , Humanos , Corpos de Inclusão/ultraestrutura , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/patologia , Músculo Esquelético/ultraestrutura , Linhagem , Estudos Retrospectivos , Proteína com ValosinaRESUMO
Studies of Drosophila and mammals have revealed the importance of insulin signaling through phosphatidylinositol 3-kinase and the serine/threonine kinase Akt/protein kinase B for the regulation of cell, organ, and organismal growth. In mammals, three highly conserved proteins, Akt1, Akt2, and Akt3, comprise the Akt family, of which the first two are required for normal growth and metabolism, respectively. Here we address the function of Akt3. Like Akt1, Akt3 is not required for the maintenance of normal carbohydrate metabolism but is essential for the attainment of normal organ size. However, in contrast to Akt1-/- mice, which display a proportional decrease in the sizes of all organs, Akt3-/- mice present a selective 20% decrease in brain size. Moreover, although Akt1- and Akt3-deficient brains are reduced in size to approximately the same degree, the absence of Akt1 leads to a reduction in cell number, whereas the lack of Akt3 results in smaller and fewer cells. Finally, mammalian target of rapamycin signaling is attenuated in the brains of Akt3-/- but not Akt1-/- mice, suggesting that differential regulation of this pathway contributes to an isoform-specific regulation of cell growth.
Assuntos
Encéfalo/enzimologia , Encéfalo/crescimento & desenvolvimento , Proteínas Oncogênicas/fisiologia , Proteínas Serina-Treonina Quinases/fisiologia , Animais , Glicemia/análise , Peso Corporal/genética , Peso Corporal/fisiologia , Encéfalo/citologia , Feminino , Glucose/metabolismo , Teste de Tolerância a Glucose , Insulina/sangue , Insulina/metabolismo , Masculino , Camundongos , Camundongos Knockout , Miocárdio/citologia , Proteínas Oncogênicas/genética , Tamanho do Órgão/genética , Tamanho do Órgão/fisiologia , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/fisiologia , Proteínas Proto-Oncogênicas c-akt , Proteínas Quinases S6 Ribossômicas/metabolismoRESUMO
Filamentous tau inclusions in neurons and glia are neuropathological hallmarks of tauopathies. The discovery of microtubule-associated protein tau gene mutations that are pathogenic for a heterogenous group of neurodegenerative disorders, called frontotemporal dementia and parkinsonism linked to chromosome-17 (FTDP-17), directly implicate tau abnormalities in the onset/progression of disease. Although the role of tau pathology in neurons in disease pathogenesis is well accepted, the contribution of glial pathology is essentially unknown. We recently generated a transgenic (Tg) mouse model of tau pathology in astrocytes by expressing the human tau protein under the control of the glial fibrillary acidic protein (GFAP) promoter. Both wild-type and FTDP-17 mutant GFAP/tau Tg animals manifest an age-dependent accumulation of tau inclusions in astrocytes that resembles the pathology observed in human tauopathies. We further demonstrate that both strains of Tg mice manifest compromised motor function that correlates with altered expression of the glial glutamate-aspartate transporter and occurs before the development of tau pathology. Subsequently, the Tg mice manifest additional deficits in neuromuscular strength that correlates with reduced expression of glutamate transporter-1 (GLT-1) and occurs concurrent with tau inclusion pathology. Reduced GLT-1 expression was associated with a progressive decrease in sodium-dependent glutamate transport capacity. Reductions in GLT-1 expression were also observed in corticobasal degeneration, a tauopathy with prominent pathology in astrocytes. Less robust changes were observed in Alzheimer's disease in which neuronal tau pathology predominates. Thus, these Tg mice recapitulate features of astrocytic pathology observed in tauopathies and implicate a role for altered astrocyte function in the pathogenesis of these disorders.
Assuntos
Astrócitos/metabolismo , Transportador 2 de Aminoácido Excitatório/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Tauopatias/metabolismo , Substituição de Aminoácidos , Animais , Sistema Nervoso Central/metabolismo , Modelos Animais de Doenças , Transportador 1 de Aminoácido Excitatório/deficiência , Transportador 1 de Aminoácido Excitatório/fisiologia , Transportador 2 de Aminoácido Excitatório/deficiência , Regulação da Expressão Gênica , Proteína Glial Fibrilar Ácida/genética , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Debilidade Muscular/genética , Debilidade Muscular/fisiopatologia , Mutação de Sentido Incorreto , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/fisiologia , Mutação Puntual , Regiões Promotoras Genéticas , Proteínas Recombinantes de Fusão/metabolismo , Proteínas tauRESUMO
Frontotemporal dementia with inclusion body myopathy and Paget disease of bone is a rare, autosomal-dominant disorder caused by mutations in the gene valosin-containing protein (VCP). The CNS pathology is characterized by a novel pattern of ubiquitin pathology distinct from sporadic and familial frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) without VCP mutations. TAR DNA binding protein 43 (TDP-43) was recently identified as a major disease protein in the ubiquitin-positive inclusions of sporadic and familial FTLD-U. To determine whether the ubiquitin pathology associated with mutations in VCP is characterized by the accumulation of TDP-43, we analyzed TDP-43 in the CNS pathology of five patients with VCP gene mutations. Accumulations of TDP-43 colocalized with ubiquitin pathology in inclusion body myopathy and Paget disease of bone, including both intranuclear inclusions and dystrophic neurites. Similar to FTLD-U, phosphorylated TDP-43 was detected only in insoluble brain extracts from affected brain regions. Identification of TDP-43, but not VCP, within ubiquitin-positive inclusions supports the hypothesis that VCP gene mutations lead to a dominant negative loss or alteration of VCP function culminating in impaired degradation of TDP-43. TDP-43 is a common pathologic substrate linking a variety of distinct patterns of FTLD-U pathology caused by different genetic alterations.
Assuntos
Adenosina Trifosfatases/genética , Proteínas de Ciclo Celular/genética , Córtex Cerebral/metabolismo , Proteínas de Ligação a DNA/metabolismo , Demência/genética , Demência/metabolismo , Ubiquitina/metabolismo , Idoso , Córtex Cerebral/patologia , Demência/patologia , Feminino , Humanos , Corpos de Inclusão/genética , Corpos de Inclusão/metabolismo , Corpos de Inclusão/patologia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Miosite de Corpos de Inclusão/genética , Miosite de Corpos de Inclusão/metabolismo , Miosite de Corpos de Inclusão/patologia , Neurônios/metabolismo , Neurônios/patologia , Osteíte Deformante/genética , Osteíte Deformante/metabolismo , Osteíte Deformante/patologia , Proteína com ValosinaRESUMO
BACKGROUND: Patients with frontotemporal dementia due to mutation of progranulin may have a distinct phenotype. OBJECTIVE: To identify distinct clinical and pathologic features of patients with frontotemporal dementia who have mutations of progranulin (GRN). DESIGN: Retrospective clinical-pathologic study. SETTING: Academic medical center. PATIENTS: Twenty-eight patients with frontotemporal dementia, including 9 with GRN mutations (4 autopsy cases and 5 with only clinical information) and 19 with the identical pathologic diagnosis--frontotemporal lobar degeneration with ubiquitin-positive and tau-negative inclusions (FTLD-U)--and no GRN mutations. MAIN OUTCOME MEASURES: Demographic, symptom, neuropsychological, and autopsy characteristics. RESULTS: Patients with and without a GRN mutation have similar demographic features, although family history is significantly more common in patients with frontotemporal dementia and a GRN mutation. Both patient groups have frequent social and personality complaints. Neuropsychological evaluation reveals a significant recognition memory deficit in patients with a GRN mutation but a significant language deficit only in patients without a GRN mutation. At autopsy, the semiquantitative burden of ubiquitin abnormality is relatively modest in both groups of patients. CONCLUSION: Patients with a GRN mutation differ clinically from those with the same pathologic diagnosis but no GRN mutation.
Assuntos
Demência/genética , Demência/psicologia , Lobo Frontal , Peptídeos e Proteínas de Sinalização Intercelular/genética , Mutação , Lobo Temporal , Idoso , Encéfalo/metabolismo , Encéfalo/patologia , Demência/metabolismo , Demência/patologia , Feminino , Humanos , Relações Interpessoais , Transtornos da Linguagem/etiologia , Masculino , Transtornos da Memória/etiologia , Transtornos da Memória/psicologia , Pessoa de Meia-Idade , Testes Neuropsicológicos , Transtornos da Personalidade/etiologia , Progranulinas , Reconhecimento Psicológico , Estudos Retrospectivos , Ubiquitina/metabolismoRESUMO
BACKGROUND: TDP-43 is a major ubiquitinated disease protein in the pathologic condition of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). OBJECTIVE: To investigate the demographic, clinical, and neuropsychological features associated with subtypes of FTLD-U with TDP-43 inclusions (FTLD-U/TDP-43). DESIGN: Retrospective clinical-pathologic study. SETTING: Academic medical center. Patients Twenty-three patients with histopathologically proven FTLD-U. MAIN OUTCOME MEASURES: Demographic, symptom, neuropsychological, and autopsy characteristics. RESULTS: There are notably different clinical and neuropsychological patterns of impairment in FTLD-U subtypes. Patients with FTLD-U/TDP-43 characterized by numerous neuronal intracytoplasmic inclusions have shorter survival; patients with FTLD-U/TDP-43 featuring numerous neurites have difficulty with object naming; and patients with FTLD-U/TDP-43 in whom neuronal intranuclear inclusions are present have substantial executive deficits. There are also different anatomical distributions of ubiquitin pathologic features in FTLD-U subgroups, consistent with their cognitive deficits. CONCLUSION: Distinct TDP-43 profiles may affect clinical phenotypes differentially in patients with FTLD-U.
Assuntos
Proteínas de Ligação a DNA/genética , Demência/genética , Demência/patologia , Corpos de Inclusão/genética , Corpos de Inclusão/patologia , Ubiquitina/metabolismo , Idoso , Autopsia , Encéfalo/patologia , Cognição/fisiologia , Interpretação Estatística de Dados , Demência/psicologia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Fenótipo , Desempenho Psicomotor/fisiologia , Estudos RetrospectivosRESUMO
BACKGROUND: Clinical-pathologic studies are crucial to understanding brain-behavior relations and improving diagnostic accuracy in neurodegenerative diseases. OBJECTIVE: To establish clinical, neuropsychological, and imaging features of clinically diagnosed patients with frontotemporal dementia (FTD) that help discriminate between pathologically determined tau-positive FTD, tau-negative FTD, and frontal-variant Alzheimer disease. DESIGN: Retrospective clinical-pathologic survey. SETTING: Academic medical center. Patients Sixty-one participants with the clinical diagnosis of a frontotemporal spectrum disorder who underwent a neuropsychological evaluation and had an autopsy-confirmed disease. MAIN OUTCOME MEASURES: Neuropsychological performance and high-resolution structural magnetic resonance imaging (MRI). RESULTS: Distinguishing features of patients with tau-positive FTD include visual perceptual-spatial difficulty and an extrapyramidal disorder significantly more often than other patients, significant cortical atrophy in the frontal and parietal regions as evidenced on MRI, and the burden of pathology is greatest in the frontal and parietal regions. Patients with tau-negative FTD are distinguished by their greater difficulties with social, language, and verbally mediated executive functions, significant cortical atrophy in the frontal and temporal regions as evidenced on MRI, and significant frontal and temporal pathology. Patients with Alzheimer disease at autopsy have significantly impaired delayed recall during episodic memory testing; atrophy that involves temporal areas, including the hippocampus, as evidenced on MRI; and widely distributed pathology including the medial temporal structures. A discriminant function analysis grouped patients on the basis of clinical and neuropsychological features with 87.5% accuracy. CONCLUSION: Clinical, neuropsychological, and imaging profiles can contribute to accurate antemortem diagnosis in FTD.
Assuntos
Demência/patologia , Pacientes Internados , Proteínas tau/metabolismo , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Autopsia/métodos , Mapeamento Encefálico , Demência/fisiopatologia , Feminino , Inquéritos Epidemiológicos , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Estudos RetrospectivosRESUMO
Abundant filamentous tau inclusions in oligodendrocytes (OLGs) are hallmarks of neurodegenerative tauopathies, including sporadic corticobasal degeneration and hereditary frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). However, mechanisms of neurodegeneration in these tauopathies are unclear in part because of the lack of animal models for experimental analysis. We address this by generating transgenic (Tg) mice expressing human tau exclusively in OLGs using the 2',3'-cyclic nucleotide 3'-phosphodiesterase promoter. Filamentous OLG tau inclusions developed in these Tg mice as a result of human tau expression in OLGs, especially those expressing the FTDP-17 human P301L mutant tau. Notably, structural disruption of myelin and axons preceded the emergence of thioflavin-S positive tau inclusions in OLGs, but impairments in axonal transport occurred even earlier, whereas motor deficits developed subsequently, especially in Tg mice with the highest tau expression levels. These data suggest that the accumulation of tau in OLG cause neurodegeneration, and we infer they do so by disrupting axonal transport. We suggest that similar defects may also occur in sporadic and hereditary human tauopathies with OLG tau pathologies.
Assuntos
Axônios/metabolismo , Modelos Animais de Doenças , Degeneração Neural/metabolismo , Oligodendroglia/metabolismo , Tauopatias/metabolismo , Proteínas tau/biossíntese , Animais , Axônios/patologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Degeneração Neural/genética , Degeneração Neural/patologia , Neuroglia/metabolismo , Neuroglia/patologia , Oligodendroglia/patologia , Tauopatias/genética , Tauopatias/patologia , Proteínas tau/genéticaRESUMO
Filamentous tau inclusions in neurons and glia are neuropathological hallmarks of sporadic and familial tauopathies. Because tau gene mutations are pathogenic for the autosomal dominant tauopathy "frontotemporal dementia and parkinsonism linked to chromosome 17," tau abnormalities are implicated directly in the onset and/or progression of disease. Although filamentous tau aggregates are acknowledged to play roles in degenerative mechanisms resulting in neuron loss, the contributions of glial tau pathology to neurodegeneration remain essentially unexplored. To begin to elucidate the role of glial pathology in tauopathies, we generated a transgenic (Tg) mouse model of astrocytic tau pathology by expressing the human tau protein driven by the glial fibrillary acidic protein (GFAP) promoter. Whereas endogenous tau was not detected in astrocytes of control mice, in GFAP/tau Tg mice there was robust astrocytic tau expression that was associated with a redistribution of the GFAP network. Subsequently, there was an age-dependent accumulation of tau pathology in astrocytes that was Gallyas and variably thioflavine S positive as observed in many tauopathies. The tau pathology in these Tg mice was abnormally phosphorylated, ubiquitinated, and filamentous, and the emergence of this pathology coincided with accumulation of insoluble tau protein. Furthermore, in regions with robust astrocytic tau pathology, there was mild blood- brain barrier disruption, induction of low-molecular-weight heat shock proteins, and focal neuron degeneration. Thus, these Tg mice recapitulate key features of astrocytic pathology observed in human tauopathies and demonstrate functional consequences of this pathology including neuron degeneration in the absence of neuronal tau inclusions.
Assuntos
Astrócitos/metabolismo , Astrócitos/patologia , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Proteínas tau/metabolismo , Fatores Etários , Animais , Axônios/metabolismo , Axônios/patologia , Axônios/ultraestrutura , Barreira Hematoencefálica/patologia , Western Blotting/métodos , Encéfalo/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Expressão Gênica/fisiologia , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Imuno-Histoquímica/métodos , Camundongos , Camundongos Transgênicos , Microscopia Imunoeletrônica/métodos , Degeneração Neural/genética , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/ultraestrutura , Proteínas de Neurofilamentos/metabolismo , Ubiquitina/metabolismo , Proteínas tau/genéticaRESUMO
Frontotemporal dementia (FTD) with inclusion body myopathy and Paget disease of bone (IBMPFD) is a rare, autosomal-dominant disorder caused by mutations in the valosin-containing protein (VCP) gene, a member of the AAA-ATPase gene superfamily. The neuropathology associated with sporadic FTD is heterogeneous and includes tauopathies and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). However, there is limited information on the neuropathology in IBMPFD. We performed a detailed, systematic analysis of the neuropathologic changes in 8 patients with VCP mutations. A novel pattern of ubiquitin pathology was identified in IBMPFD that was distinct from sporadic and familial FTLD-U without VCP gene mutations. This was characterized by ubiquitin-positive neuronal intranuclear inclusions and dystrophic neurites. In contrast to FTLD-U, only rare intracytoplasmic inclusions were identified. The ubiquitin pathology was abundant in the neocortex, less robust in limbic and subcortical nuclei, and absent in the dentate gyrus. Only rare inclusions were detected with antibodies to VCP and there was no biochemical alteration in the VCP protein. VCP is associated with a variety of cellular activities, including regulation of the ubiquitin-proteasome system. Our findings are consistent with the hypothesis that the pathology associated with VCP gene mutations is the result of impairment of ubiquitin-based degradation pathways.
Assuntos
Proteínas de Ciclo Celular/genética , Demência/genética , Demência/metabolismo , Mutação/genética , Ubiquitina/metabolismo , Adenosina Trifosfatases , Western Blotting/métodos , Demência/patologia , Feminino , Humanos , Imuno-Histoquímica/métodos , Masculino , Miosite de Corpos de Inclusão/genética , Miosite de Corpos de Inclusão/patologia , Osteíte Deformante/genética , Osteíte Deformante/patologia , Proteína com ValosinaRESUMO
The endoplasmic reticulum responds to stress by initiating a cascade of events known as the 'unfolded-protein response' (UPR). The accumulation of misfolded proteins in the leukodystrophy Pelizaeus-Merzbacher disease activates this stress response, resulting in apoptosis of oligodendrocytes. Although it remains uncertain whether the UPR plays a mechanistic role in prototypical neurodegenerative disorders such as Alzheimer's disease, this is plausible because misfolded proteins are directly implicated in the pathogenesis of these disorders.
Assuntos
Retículo Endoplasmático/química , Retículo Endoplasmático/metabolismo , Doenças Neurodegenerativas/fisiopatologia , Conformação Proteica , Dobramento de Proteína , Estresse Fisiológico/fisiopatologia , Adaptação Fisiológica , Doença de Alzheimer/fisiopatologia , Animais , Apoptose , Humanos , Proteínas de Membrana/fisiologia , Camundongos , Doença de Parkinson/fisiopatologia , Doença de Pelizaeus-Merzbacher/fisiopatologiaRESUMO
Orexin neuropeptides regulate sleep/wake through orexin receptors (OX1R, OX2R); OX2R is the predominant mediator of arousal promotion. The potential for single OX2R antagonism to effectively promote sleep has yet to be demonstrated in humans. MK-1064 is an OX2R-single antagonist. Preclinically, MK-1064 promotes sleep and increases both rapid eye movement (REM) and non-REM (NREM) sleep in rats at OX2R occupancies higher than the range observed for dual orexin receptor antagonists. Similar to dual antagonists, MK-1064 increases NREM and REM sleep in dogs without inducing cataplexy. Two Phase I studies in healthy human subjects evaluated safety, tolerability, pharmacokinetics and sleep-promoting effects of MK-1064, and demonstrated dose-dependent increases in subjective somnolence (via Karolinska Sleepiness Scale and Visual Analogue Scale measures) and sleep (via polysomnography), including increased REM and NREM sleep. Thus, selective OX2R antagonism is sufficient to promote REM and NREM sleep across species, similarly to that seen with dual orexin receptor antagonism.
Assuntos
Antagonistas dos Receptores de Orexina/administração & dosagem , Receptores de Orexina/metabolismo , Medicamentos Indutores do Sono/administração & dosagem , Fases do Sono/efeitos dos fármacos , Animais , Cães , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Camundongos , Antagonistas dos Receptores de Orexina/farmacologia , Polissonografia , Ratos , Medicamentos Indutores do Sono/farmacologia , Sono REM/efeitos dos fármacosRESUMO
ß-Amyloid (Aß) peptides are thought to be critically involved in the etiology of Alzheimer's disease (AD). The aspartyl protease ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) is required for the production of Aß, and BACE1 inhibition is thus an attractive target for the treatment of AD. We show that verubecestat (MK-8931) is a potent, selective, structurally unique BACE1 inhibitor that reduced plasma, cerebrospinal fluid (CSF), and brain concentrations of Aß40, Aß42, and sAPPß (a direct product of BACE1 enzymatic activity) after acute and chronic administration to rats and monkeys. Chronic treatment of rats and monkeys with verubecestat achieved exposures >40-fold higher than those being tested in clinical trials in AD patients yet did not elicit many of the adverse effects previously attributed to BACE inhibition, such as reduced nerve myelination, neurodegeneration, altered glucose homeostasis, or hepatotoxicity. Fur hypopigmentation was observed in rabbits and mice but not in monkeys. Single and multiple doses were generally well tolerated and produced reductions in Aß40, Aß42, and sAPPß in the CSF of both healthy human subjects and AD patients. The human data were fit to an amyloid pathway model that provided insight into the Aß pools affected by BACE1 inhibition and guided the choice of doses for subsequent clinical trials.