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1.
Int J Cosmet Sci ; 40(1): 1-15, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29057483

RESUMO

The marine environment represents an underexploited resource for the discovery of novel products, despite its high level of biological and chemical diversity. With increasing awareness of the harmful effects of chronic ultraviolet exposure, and a universal desire to improve cosmetic appearance, the market for new cosmetic ingredients is growing, and current trends have generated a greater demand for products sourced from the environment. A growing number of novel molecules from marine flora and fauna exhibit potent and effective dermatological activities. Secondary metabolites isolated from macroalgae, including carotenoids and polyphenols, have demonstrated antioxidant, anti-ageing and anti-inflammatory activities. In addition, marine extremophilic bacteria have recently been shown to produce bioactive exopolymeric molecules, some of which have been commercialized. Available data on their activities show significant antioxidant, moisturizing and anti-ageing activities, but a more focussed investigation into their mechanisms and applications is required. This review surveys the reported biological activities of an emerging and growing portfolio of marine molecules that show promise in the treatment of cosmetic skin problems including ultraviolet damage, ageing and cutaneous dryness.


Assuntos
Organismos Aquáticos/química , Cosméticos/química , Cosméticos/farmacologia , Cosméticos/uso terapêutico , Emolientes/uso terapêutico , Humanos , Hiperpigmentação/terapia , Ictiose/terapia , Água do Mar , Pele/efeitos dos fármacos , Pele/fisiopatologia , Pele/efeitos da radiação , Envelhecimento da Pele/efeitos dos fármacos , Protetores Solares/administração & dosagem , Raios Ultravioleta/efeitos adversos
2.
Neuropathol Appl Neurobiol ; 42(2): 153-66, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26095752

RESUMO

AIMS: Polyglutamine (polyQ) diseases are characterized by the expansion of a polymorphic glutamine sequence in disease-specific proteins and exhibit aggregation of these proteins. This is combated by the cellular protein quality control (PQC) system, consisting of chaperone-mediated refolding as well as proteasomal and lysosomal degradation pathways. Our recent study in the polyQ disease spinocerebellar ataxia type 3 (SCA3) suggested a distinct pattern of protein aggregation and PQC dysregulation. METHODS: To corroborate these findings we have investigated immunohistochemically stained 5 µm sections from different brain areas of Huntington's disease (HD) and SCA3 patients. RESULTS: Irrespective of disease and brain region, we observed peri- and intranuclear polyQ protein aggregates. A subset of neurones with intranuclear inclusions bodies exhibited signs of proteasomal dysfunction, up-regulation of HSPA1A and re-distribution of DNAJB1. The extent of the observed effects varied depending on brain area and disease protein. CONCLUSIONS: Our results suggest a common sequence, in which formation of cytoplasmic and nuclear inclusions precede proteasomal impairment and induction of the cellular stress response. Clearly, impairment of the PQC is not the primary cause for inclusion formation, but rather a consequence that might contribute to neuronal dysfunction and death. Notably, the inclusion pathology is not directly correlated to the severity of the degeneration in different areas, implying that different populations of neurones respond to polyQ aggregation with varying efficacy and that protein aggregation outside the neuronal perikaryon (e.g. axonal aggregates) or other effects of polyQ aggregation, which are more difficult to visualize, may contribute to neurodegeneration.


Assuntos
Encéfalo/patologia , Doença de Huntington/patologia , Doença de Machado-Joseph/patologia , Peptídeos/metabolismo , Agregação Patológica de Proteínas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Encéfalo/metabolismo , Feminino , Humanos , Doença de Huntington/metabolismo , Imuno-Histoquímica , Corpos de Inclusão Intranuclear/metabolismo , Corpos de Inclusão Intranuclear/patologia , Doença de Machado-Joseph/metabolismo , Masculino , Pessoa de Meia-Idade , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Neurônios/patologia , Agregação Patológica de Proteínas/metabolismo
3.
Neuropathol Appl Neurobiol ; 39(6): 634-43, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23363055

RESUMO

AIMS: Spinocerebellar ataxia type 2 (SCA2) belongs to the CAG repeat or polyglutamine diseases. Along with a large variety of motor, behavioural and neuropsychological symptoms the clinical picture of patients suffering from this autosomal dominantly inherited ataxia may also include deficits of attention, impairments of memory, as well as frontal-executive and visuospatial dysfunctions. As the possible morphological correlates of these cognitive SCA2 deficits are unclear we examined the cholinergic basal forebrain nuclei, which are believed to be crucial for several aspects of normal cognition and may contribute to impairments of cognitive functions under pathological conditions. METHODS: We studied pigment-Nissl-stained thick tissue sections through the cholinergic basal forebrain nuclei (that is, medial septal nucleus, nuclei of the diagonal band of Broca, basal nucleus of Meynert) of four clinically diagnosed and genetically confirmed SCA2 patients and of 13 control individuals according to the pathoanatomical approach. The pathoanatomical results were confirmed by additional quantitative investigations of these nuclei in the SCA2 patients and four age- and gender-matched controls. RESULTS: Our study revealed a severe and consistent neuronal loss in all of the cholinergic basal forebrain nuclei (medial septal nucleus: 72%; vertical nucleus of the diagonal band of Broca: 74%; horizontal limb of the diagonal band of Broca: 72%; basal nucleus of Meynert: 86%) of the SCA2 patients studied. Damage to the basal forebrain nuclei was associated with everyday relevant cognitive deficits only in our SCA2 patient with an additional Braak and Braak stage V Alzheimer's disease (AD)-related tau pathology. CONCLUSIONS: The findings of the present study: (1) indicate that the mutation and pathological process underlying SCA2 play a causative role for this severe degeneration of the cholinergic basal forebrain nuclei and (2) may suggest that degeneration of the cholinergic basal forebrain nuclei per se is not sufficient to cause profound and global dementia detrimental to everyday practice and activities of daily living.


Assuntos
Núcleo Basal de Meynert/patologia , Neurônios Colinérgicos/patologia , Feixe Diagonal de Broca/patologia , Núcleos Septais/patologia , Ataxias Espinocerebelares/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
4.
Nat Genet ; 8(2): 136-40, 1994 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-7842011

RESUMO

Episodic ataxia (EA) is a rare, familial disorder producing attacks of generalized ataxia, with normal or near-normal neurological function between attacks. One type of EA is characterized by brief episodes of ataxia with myokymia (rippling of muscles) evident between attacks. Linkage studies in four such families suggested localization of an EA/myokymia gene near the voltage gated K+ channel gene, KCNA1 (Kv1.1), on chromosome 12p. Mutation analysis of the KCNA1 coding region in these families identified four different missense point mutations present in the heterozygous state, indicating that EA/myokymia can result from mutations in this gene.


Assuntos
Ataxia/genética , Fasciculação/genética , Mutação Puntual , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Canais de Potássio/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Mapeamento Cromossômico , Cromossomos Humanos Par 12 , Proteínas de Drosophila , Drosophila melanogaster/genética , Feminino , Genes , Humanos , Canal de Potássio Kv1.1 , Masculino , Camundongos , Dados de Sequência Molecular , Linhagem , Canais de Potássio/química , Canais de Potássio/deficiência , Canais de Potássio/fisiologia , Conformação Proteica , Ratos , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Superfamília Shaker de Canais de Potássio , Síndrome
5.
Neuropathol Appl Neurobiol ; 38(1): 39-53, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21696420

RESUMO

AIMS: HSPB8 is a small heat shock protein that forms a complex with the co-chaperone BAG3. Overexpression of the HSPB8-BAG3 complex in cells stimulates autophagy and facilitates the clearance of mutated aggregation-prone proteins, whose accumulation is a hallmark of many neurodegenerative disorders. HSPB8-BAG3 could thus play a protective role in protein aggregation diseases and might be specifically upregulated in response to aggregate-prone protein-mediated toxicity. Here we analysed HSPB8-BAG3 expression levels in post-mortem human brain tissue from patients suffering of the following protein conformation disorders: Alzheimer's disease, Parkinson's disease, Huntington's disease and spinocerebellar ataxia type 3 (SCA3). METHODS: Western blotting and immunohistochemistry techniques were used to analyse HSPB8 and BAG3 expression levels in fibroblasts from SCA3 patients and post-mortem brain tissues, respectively. RESULTS: In all diseases investigated, we observed a strong upregulation of HSPB8 and a moderate upregulation of BAG3 specifically in astrocytes in the cerebral areas affected by neuronal damage and degeneration. Intriguingly, no significant change in the HSPB8-BAG3 expression levels was observed within neurones, irrespective of their localization or of the presence of proteinaceous aggregates. CONCLUSIONS: We propose that the upregulation of HSPB8 and BAG3 may enhance the ability of astrocytes to clear aggregated proteins released from neurones and cellular debris, maintain the local tissue homeostasis and/or participate in the cytoskeletal remodelling that astrocytes undergo during astrogliosis.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Astrócitos/metabolismo , Proteínas de Choque Térmico/biossíntese , Doenças Neurodegenerativas/metabolismo , Proteínas Serina-Treonina Quinases/biossíntese , Proteínas Reguladoras de Apoptose , Western Blotting , Imunofluorescência , Humanos , Imuno-Histoquímica , Chaperonas Moleculares , Regulação para Cima
6.
Neuropathol Appl Neurobiol ; 38(7): 665-80, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22309224

RESUMO

AIMS: Spinocerebellar ataxia type 1 (SCA1) represents the first molecular genetically characterized autosomal dominantly inherited cerebellar ataxia and is assigned to the CAG-repeat or polyglutamine diseases. Owing to limited knowledge about SCA1 neuropathology, appropriate pathoanatomical correlates of a large variety of SCA1 disease symptoms are missing and the neuropathological basis for further morphological and experimental SCA1 studies is still fragmentary. METHODS: In the present study, we investigated for the first time serial tissue sections through the complete brains of clinically diagnosed and genetically confirmed SCA1 patients. RESULTS: Brain damage in the three SCA1 patients studied went beyond the well-known brain predilection sites of the underlying pathological process. Along with neuronal loss in the primary motor cortex, it included widespread degeneration of gray components of the basal forebrain, thalamus, brainstem and cerebellum, as well as of white matter components in the cerebellum and brainstem. It involved the motor cerebellothalamocortical and basal ganglia-thalamocortical circuits, the visual, auditory, somatosensory, oculomotor, vestibular, ingestion-related, precerebellar, basal forebrain cholinergic and midbrain dopaminergic systems. CONCLUSIONS: These findings show for the first time that the extent and severity of brain damage in SCA1 is very similar to that of clinically closely related spinocerebellar ataxias (that is, SCA2, SCA3 and SCA7). They offer suitable explanations for poorly understood SCA1 disease symptoms and will facilitate the interpretation of further morphological and experimental SCA1 studies.


Assuntos
Encéfalo/patologia , Degeneração Neural/patologia , Ataxias Espinocerebelares/patologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/metabolismo , Peptídeos/metabolismo
7.
Neuropathol Appl Neurobiol ; 38(6): 548-58, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21916928

RESUMO

AIMS: A characteristic of polyglutamine diseases is the increased propensity of disease proteins to aggregate, which is thought to be a major contributing factor to the underlying neurodegeneration. Healthy cells contain mechanisms for handling protein damage, the protein quality control, which must be impaired or inefficient to permit proteotoxicity under pathological conditions. METHODS: We used a quantitative analysis of immunohistochemistry of the pons of eight patients with the polyglutamine disorder spinocerebellar ataxia type 3. We employed the anti-polyglutamine antibody 1C2, antibodies against p62 that is involved in delivering ubiquitinated protein aggregates to autophagosomes, antibodies against the chaperones HSPA1A and DNAJB1 and the proteasomal stress marker UBB⁺¹. RESULTS: The 1C2 antibody stained neuronal nuclear inclusions (NNIs), diffuse nuclear staining (DNS), granular cytoplasmic staining (GCS) and combinations, with reproducible distribution. P62 always co-localized with 1C2 in NNI. DNS and GCS co-stained with a lower frequency. UBB⁺¹ was present in a subset of neurones with NNI. A subset of UBB⁺¹-containing neurones displayed increased levels of HSPA1A, while DNAJB1 was sequestered into the NNI. CONCLUSION: Based on our results, we propose a model for the aggregation-associated pathology of spinocerebellar ataxia type 3: GCS and DNS aggregation likely represents early stages of pathology, which progresses towards formation of p62-positive NNI. A fraction of NNI exhibits UBB⁺¹ staining, implying proteasomal overload at a later stage. Subsequently, the stress-inducible HSPA1A is elevated while DNAJB1 is recruited into NNIs. This indicates that the stress response is only induced late when all endogenous protein quality control systems have failed.


Assuntos
Doença de Machado-Joseph/metabolismo , Neurônios/metabolismo , Ponte/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Proteínas de Choque Térmico HSP40/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Humanos , Imuno-Histoquímica , Corpos de Inclusão Intranuclear/metabolismo , Corpos de Inclusão Intranuclear/patologia , Doença de Machado-Joseph/patologia , Masculino , Pessoa de Meia-Idade , Neurônios/patologia , Ponte/patologia , Proteína Sequestossoma-1 , Ubiquitina/metabolismo
8.
Cerebellum ; 11(3): 749-60, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22198871

RESUMO

The cerebellum is one of the well-known targets of the pathological processes underlying spinocerebellar ataxia type 2 (SCA2) and type 3 (SCA3). Despite its pivotal role for the clinical pictures of these polyglutamine ataxias, no pathoanatomical studies of serial tissue sections through the cerebellum have been performed in SCA2 and SCA3 so far. Detailed pathoanatomical data are an important prerequisite for the identification of the initial events of the underlying disease processes of SCA2 and SCA3 and the reconstruction of its spread through the brain. In the present study, we performed a pathoanatomical investigation of serial thick tissue sections through the cerebellum of clinically diagnosed and genetically confirmed SCA2 and SCA3 patients. This study demonstrates that the cerebellar Purkinje cell layer and all four deep cerebellar nuclei consistently undergo considerable neuronal loss in SCA2 and SCA3. These cerebellar findings contribute substantially to the pathogenesis of clinical symptoms (i.e., dysarthria, intention tremor, oculomotor dysfunctions) of SCA2 and SCA3 patients and may facilitate the identification of the initial pathological alterations of the pathological processes of SCA2 and SCA3 and reconstruction of its spread through the brain.


Assuntos
Cerebelo/patologia , Degeneração Neural/patologia , Ataxias Espinocerebelares/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Atrofia , Córtex Cerebelar/patologia , Núcleos Cerebelares/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Bainha de Mielina/patologia , Células de Purkinje/patologia , Ataxias Espinocerebelares/genética , Tomografia Computadorizada por Raios X , Adulto Jovem
9.
Eur J Neurosci ; 32(5): 760-70, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20726892

RESUMO

In polyglutamine disorders, the length of the expanded CAG repeat shows a strong inverse correlation with the age at disease onset, yet up to 50% of the variation in age of onset is determined by other additional factors. Here, we investigated whether variations in the expression of heat shock proteins (HSP) are related to differences in the age of onset in patients with spinocerebellar ataxia (SCA)3. Hereto, we analysed the protein expression levels of HSPA1A (HSP70), HSPA8 (HSC70), DNAJB (HSP40) and HSPB1 (HSP27) in fibroblasts from patients and healthy controls. HSPB1 levels were significantly upregulated in fibroblasts from patients with SCA3, but without relation to age of onset. Exclusively for expression of DNAJB family members, a correlation was found with the age of onset independent of the length of the CAG repeat expansion. This indicates that DNAJB members might be contributors to the variation in age of onset and underlines the possible use of DNAJB proteins as therapeutic targets.


Assuntos
Proteínas de Choque Térmico HSP40/biossíntese , Proteínas de Choque Térmico/biossíntese , Doença de Machado-Joseph/genética , Adulto , Idade de Início , Idoso , Ataxina-3 , Técnicas de Cultura de Células , Linhagem Celular , Linhagem Celular Transformada , Feminino , Fibroblastos/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/biossíntese , Proteínas Nucleares/metabolismo , Proteínas Repressoras/biossíntese , Proteínas Repressoras/metabolismo , Expansão das Repetições de Trinucleotídeos , Regulação para Cima
10.
Neuropathol Appl Neurobiol ; 35(1): 4-15, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19187058

RESUMO

Recent progress in oculomotor research has enabled new insights into the functional neuroanatomy of the human premotor oculomotor brainstem network. In the present review, we provide an overview of its functional neuroanatomy and summarize the broad range of oculomotor dysfunctions that may occur in Huntington's disease (HD) patients. Although some of these oculomotor symptoms point to an involvement of the premotor oculomotor brainstem network in HD, no systematic analysis of this functional system has yet been performed in brains of HD patients. Therefore, its exact contribution to oculomotor symptoms in HD remains unclear. A possible strategy to clarify this issue is the use of unconventional 100-microm-thick serial tissue sections stained for Nissl substance and lipofuscin pigment (Nissl-pigment stain according to Braak). This technique makes it possible to identify the known nuclei of the premotor oculomotor brainstem network and to study their possible involvement in the neurodegenerative process. Studies applying this morphological approach and using the current knowledge regarding the functional neuroanatomy of this human premotor oculomotor brainstem network will help to elucidate the anatomical basis of the large spectrum of oculomotor dysfunctions that are observed in HD patients. This knowledge may aid clinicians in the diagnosis and monitoring of the disease.


Assuntos
Tronco Encefálico/fisiologia , Tronco Encefálico/fisiopatologia , Movimentos Oculares/fisiologia , Lobo Frontal/fisiopatologia , Doença de Huntington/fisiopatologia , Vias Neurais/fisiopatologia , Tronco Encefálico/patologia , Lobo Frontal/patologia , Humanos , Doença de Huntington/patologia , Vias Neurais/patologia , Visão Binocular
11.
Neuropathol Appl Neurobiol ; 35(5): 515-27, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19207264

RESUMO

AIMS: Spinocerebellar ataxia type 6 (SCA6) is a late onset autosomal dominantly inherited ataxic disorder, which belongs to the group of CAG repeat, or polyglutamine, diseases. Although, it has long been regarded as a 'pure' cerebellar disease, recent clinical studies have demonstrated disease signs challenging the view that neurodegeneration in SCA6 is confined to the well-known lesions in the cerebellum and inferior olive. METHODS: We performed a systematic pathoanatomical study throughout the brains of three clinically diagnosed and genetically confirmed SCA6 patients. RESULTS: This study confirmed that brain damage in SCA6 goes beyond the known brain predilection sites. In all of the SCA6 patients studied loss of cerebellar Purkinje cells and absence of morphologically intact layer V giant Betz pyramidal cells in the primary motor cortex, as well as widespread degeneration of brainstem nuclei was present. Additional damage to the deep cerebellar nuclei was observed in two of three SCA6 patients. CONCLUSIONS: In view of the known functional role of affected central nervous grey components it is likely that their degeneration at least in part is responsible for the occurrence of a variety of SCA6 disease symptoms.


Assuntos
Encéfalo/patologia , Degeneração Neural/patologia , Ataxias Espinocerebelares/patologia , Idoso , Autopsia , Feminino , Humanos , Masculino , Linhagem , Ataxias Espinocerebelares/genética
12.
Science ; 240(4855): 1032-3, 1988 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-3285468

RESUMO

A central hypothesis in transplantation biology is that resident leukocytes expressing class II histocompatibility antigens may determine the immunogenicity of an organ. By means of a novel method to deplete the kidney of resident leukocytes, essential fatty acid deficiency (EFAD), this hypothesis was tested in an intact, vascular organ. Kidneys subjected to EFAD and thus depleted of resident Ia-positive macrophages survived and functioned when transplanted across a major histocompatibility antigen barrier in the absence of immunosuppression of the recipient. Control allografts were rejected promptly. Allografts from donors subjected to EFAD normalized their lipid composition and were repopulated with host macrophages by 5 days. Administration of Ia-positive cells at the time of transplantation established that the resident leukocyte depletion induced by EFAD was responsible for the protective effect. These observations may provide insights into the mechanisms underlying tissue immunogenicity and the population of normal tissues with resident leukocytes.


Assuntos
Ácidos Graxos Essenciais/fisiologia , Rejeição de Enxerto , Transplante de Rim , Animais , Rim/fisiologia , Fígado/análise , Macrófagos/fisiologia , Fosfolipídeos/análise , Ratos , Ratos Endogâmicos BUF , Ratos Endogâmicos Lew , Transplante Homólogo
13.
Clin Neuropathol ; 28(5): 344-9, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19788049

RESUMO

Neuronal protein aggregates are considered as pathological hallmarks of various human neurodegenerative diseases, including the so-called CAG-repeat disorders, such as spinocerebellar ataxia Type 6 (SCA6). Since the immunocytochemical findings of an initial post-mortem study using a specific antibody against the disease protein of SCA6 (i.e., pathologically altered alpha-1A subunit of the P/Q type voltage-dependent calcium channel, CACNA1A) have not been confirmed so far, the occurrence and central nervous system distribution of neuronal protein aggregates in SCA6 is still a matter of debate. Owing to the fact that the antibody against the pathologically altered CACNA1A is not commercially available, we decided to apply a recently generated p62 antibody on brain tissue from two clinically diagnosed and genetically confirmed SCA6 patients. Application of this p62 antibody revealed numerous cytoplasmic neuronal inclusions in the degenerated cerebellar dentate nucleus and inferior olive of both SCA6 patients studied, whereby a subset of these aggregates were also ubiquitin-immunopositive. In view of the known role of p62 in protein degradation as well as aggresome/sequestosome formation, the p62 aggregate formation observed in the present study suggests that SCA6 not only is associated with an impairment of the calcium channel function and an elongated polyglutamine stretch in CACNA1A, but also with a defective protein handling by the protein quality control system.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/análise , Núcleos Cerebelares/química , Corpos de Inclusão/química , Neurônios/química , Núcleo Olivar/química , Ataxias Espinocerebelares/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Idoso , Idoso de 80 Anos ou mais , Anticorpos/imunologia , Contagem de Células , Núcleos Cerebelares/patologia , Feminino , Humanos , Imuno-Histoquímica , Corpos de Inclusão/patologia , Doença de Machado-Joseph/metabolismo , Masculino , Pessoa de Meia-Idade , Neurônios/patologia , Núcleo Olivar/patologia , Células de Purkinje/química , Células de Purkinje/patologia , Proteína Sequestossoma-1 , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/patologia , Ubiquitina/metabolismo
14.
Neuropathol Appl Neurobiol ; 34(2): 155-68, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17971076

RESUMO

Spinocerebellar ataxia type 7 (SCA7) represents a rare and severe autosomal dominantly inherited ataxic disorder and is among the known CAG-repeat, or polyglutamine, diseases. In contrast to other currently known autosomal dominantly inherited ataxic disorders, SCA7 may manifest itself with different clinical courses. Because the degenerative changes evolving during these different clinical courses are not well known, many neurological disease symptoms still are unexplained. We performed an initial pathoanatomical study on unconventional thick tissue sections of the brain of a clinically diagnosed and genetically confirmed adult-onset SCA7 patient with progressive visual impairments. In this patient we observed loss of myelinated fibres in distinct central nervous fibre tracts, and widespread degeneration of the cerebellum, telencephalon, diencephalon and lower brainstem. These degenerative changes offer appropriate explanations for a variety of less-understood neurological symptoms in adult-onset SCA7 patients with visual impairments: gait, stance and limb ataxia, falls, dysarthria, dysphagia, pyramidal signs, Parkinsonian features, writing problems, impairments of saccades and smooth pursuits, altered pupillary functions, somatosensory deficits, auditory deficits and mental impairments.


Assuntos
Encéfalo/patologia , Retina/patologia , Ataxias Espinocerebelares/patologia , Ataxias Espinocerebelares/fisiopatologia , Transtornos da Visão/etiologia , Adulto , Idade de Início , Idoso , Ataxina-7 , Encéfalo/metabolismo , Feminino , Humanos , Corpos de Inclusão/metabolismo , Corpos de Inclusão/patologia , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/metabolismo , Linhagem , Retina/metabolismo , Ataxias Espinocerebelares/complicações
15.
Neuropathol Appl Neurobiol ; 34(5): 479-91, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18221259

RESUMO

AIMS: The spinocerebellar ataxia type 2 (SCA2), type 3 (SCA3) and type 7 (SCA7) are clinically characterized by progressive and severe ataxic symptoms, dysarthria, dysphagia, oculomotor impairments, pyramidal and extrapyramidal manifestations and sensory deficits. Although recent clinical studies reported additional disease signs suggesting involvement of the brainstem auditory system, this has never been studied in detail in SCA2, SCA3 or SCA7. METHODS: We performed a detailed pathoanatomical investigation of unconventionally thick tissue sections through the auditory brainstem nuclei (that is, nucleus of the inferior colliculus, nuclei of the lateral lemniscus, superior olive, cochlear nuclei) and auditory brainstem fibre tracts (that is, lateral lemniscus, trapezoid body, dorsal acoustic stria, cochlear portion of the vestibulocochlear nerve) of clinically diagnosed and genetically confirmed SCA2, SCA3 and SCA7 patients. RESULTS: Examination of unconventionally thick serial brainstem sections stained for lipofuscin pigment and Nissl material revealed a consistent and widespread involvement of the auditory brainstem nuclei in the SCA2, SCA3 and SCA7 patients studied. Serial brainstem tissue sections stained for myelin showed loss of myelinated fibres in two of the auditory brainstem fibre tracts (that is, lateral lemniscus, trapezoid body) in a subset of patients. CONCLUSIONS: The involvement of the auditory brainstem system offers plausible explanations for the auditory impairments detected in some of our and other SCA2, SCA3 and SCA7 patients upon bedside examination or neurophysiological investigation. However, further clinical studies are required to resolve the striking discrepancy between the consistent involvement of the brainstem auditory system observed in this study and the comparatively low frequency of reported auditory impairments in SCA2, SCA3 and SCA7 patients.


Assuntos
Tronco Encefálico/patologia , Ataxias Espinocerebelares/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Degeneração Neural/patologia
16.
Clin Neuropathol ; 25(6): 272-81, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-17140157

RESUMO

OBJECTIVE: We analyzed the expression of the inflammatory mediators IL-1beta, IL-1ra, IL-6 and the transcription factors IRF-1 and C/EBPdelta (previously identified in a transgenic model of spinocerebellar ataxia type 3 (SCA3) by gene expression profiling) in the central nervous system of SCA3 patients in relation to neuronal cell loss and ataxin-3-positive neuronal intranuclear inclusions (NI), to identify a putative upregulation of cytokines or microglia in SCA3 brains and to investigate whether enhanced cytokine expression was a generalized event mediating neuronal dysfunction in SCA3. MATERIALS AND METHODS: Light- and electronmicroscopic immunohistochemistry was performed on SCA3 tissues derived from five patients from unrelated families with genetically confirmed diagnosis, and six individuals without a history of neurological or inflammatory disease. RESULTS: NI were found almost exclusively in brain regions that also showed neuronal cell loss, i.e. in pons and dentate nucleus neurons, rarely in putamen and thalamus, but not in cerebral or cerebellar cortex. NI displayed an irregular surface and were mostly attached to the nucleoli. Quantitative analysis of NI in the pons revealed an inverse relation of NI and cell loss, i.e. patients with more severe neuronal cell loss had a smaller proportion of neurons with NI. Thus, formation of NI is not necessarily an indicator of cell death but could exert a protective effect. We found increased expression of IL-1beta, IL-1ra, IL-6 and C/EBPdelta only in pons and dentate nucleus neurons and both in neurons with and without NI, suggesting that NI are not a prerequisite for transcriptional changes. CONCLUSIONS: Our data suggest that the selectively affected neuronal populations in SCA3 undergo a complex alteration of gene expression independent from the formation of NI.


Assuntos
Encéfalo/patologia , Citocinas/metabolismo , Corpos de Inclusão Intranuclear/patologia , Doença de Machado-Joseph/patologia , Neurônios/patologia , Idoso , Ataxina-3 , Biomarcadores/metabolismo , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Proteína delta de Ligação ao Facilitador CCAAT/metabolismo , Morte Celular/fisiologia , Núcleo Celular/metabolismo , Núcleo Celular/patologia , Citocinas/genética , Feminino , Regulação da Expressão Gênica/fisiologia , Humanos , Imuno-Histoquímica , Fator Regulador 1 de Interferon/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Corpos de Inclusão Intranuclear/genética , Corpos de Inclusão Intranuclear/metabolismo , Doença de Machado-Joseph/metabolismo , Doença de Machado-Joseph/fisiopatologia , Masculino , Microscopia Imunoeletrônica , Pessoa de Meia-Idade , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Degeneração Neural/fisiopatologia , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Repressoras/metabolismo
17.
Cancer Res ; 55(22): 5242-50, 1995 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-7585583

RESUMO

The cell of origin of hepatocellular carcinoma (HCC) is controversial. A method for marking cells of different lineages in vivo and then determining their carcinogenic potential should resolve this issue. A retroviral vector expressing activated ras and beta-gal genes (Ras-gal) was transferred into adult rat hepatocytes in vivo, and some animals were treated with diethylnitrosamine (DEN). Bile ductule cells and the putative stem cells of the liver (the oval cells) did not appear to be transduced by this method. At 1 month after transfer, 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside staining was performed on transduced rat livers to determine the blue cluster size. Eight % of the clusters in Ras-gal-transduced, DEN-treated livers contained at least twice as many cells as the largest cluster in Ras-gal-transduced, DEN-untreated rats, demonstrating that they had acquired markedly abnormal growth properties. When the retroviral vector containing beta-gal without ras (Gal-509) was transferred into DEN-treated rats, 2.5% of the cells were present in clusters containing at least twice as many cells as the largest cluster in Gal-509-transduced, DEN-untreated animals. Thus, p21-ras may increase the percentage of cells that acquire mutations in response to DEN, or it may behave synergistically with other mutations to increase the replication rate of cells. Occasional foci in Ras-gal-transduced, DEN-treated rats had extramedullary hematopoiesis. Forty % of the Ras-gal-transduced, DEN-treated rats developed unifocal HCC, mixed HCC/cholangiocarcinoma (CC), or CC at 3-6 months after transduction, suggesting that hepatocytes can develop into HCC or CC if sufficient genetic alterations occur.


Assuntos
Genes ras , Neoplasias Hepáticas Experimentais/etiologia , Animais , Cocarcinogênese , Dietilnitrosamina , Técnicas de Transferência de Genes , Hematopoese , Neoplasias Hepáticas Experimentais/patologia , Masculino , Mutação , Fenótipo , Ratos , Ratos Endogâmicos F344
18.
J Neurosci ; 21(15): 5389-96, 2001 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-11466410

RESUMO

Spinocerebellar ataxia type 3 (SCA3) is a polyglutamine disorder caused by a CAG repeat expansion in the coding region of a gene encoding ataxin-3. To study putative alterations of gene expression induced by expanded ataxin-3, we performed PCR-based cDNA subtractive hybridization in a cell culture model of SCA3. In rat mesencephalic CSM14.1 cells stably expressing expanded ataxin-3, we found a significant upregulation of mRNAs encoding the endopeptidase matrix metalloproteinase 2 (MMP-2), the transmembrane protein amyloid precursor protein, the interleukin-1 receptor-related Fos-inducible transcript, and the cytokine stromal cell-derived factor 1alpha (SDF1alpha). Immunohistochemical studies of the corresponding or associated proteins in human SCA3 brain tissue confirmed these findings, showing increased expression of MMP-2 and amyloid beta-protein (Abeta) in pontine neurons containing nuclear inclusions. In addition, extracellular Abeta-immunoreactive deposits were detected in human SCA3 pons. Furthermore, pontine neurons of SCA3 brains strongly expressed the antiinflammatory interleukin-1 receptor antagonist, the proinflammatory cytokine interleukin-1beta, and the proinflammatory chemokine SDF1. Finally, increased numbers of reactive astrocytes and activated microglial cells were found in SCA3 pons. These results suggest that inflammatory processes are involved in the pathogenesis of SCA3.


Assuntos
Encéfalo/metabolismo , Inflamação/metabolismo , Doença de Machado-Joseph/metabolismo , Proteínas de Membrana , Proteínas do Tecido Nervoso/biossíntese , Regulação para Cima , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Ataxina-3 , Encéfalo/patologia , Células Cultivadas , Quimiocina CXCL12 , Quimiocinas CXC/genética , Quimiocinas CXC/metabolismo , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Inflamação/genética , Proteína 1 Semelhante a Receptor de Interleucina-1 , Subunidade alfa de Receptor de Interleucina-18 , Doença de Machado-Joseph/patologia , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Proteínas do Tecido Nervoso/genética , Neurônios/metabolismo , Neurônios/patologia , Proteínas Nucleares , Ponte/metabolismo , Ponte/patologia , Proteínas/genética , Proteínas/metabolismo , RNA Mensageiro/metabolismo , Ratos , Receptores de Superfície Celular , Receptores de Interleucina , Receptores de Interleucina-18 , Proteínas Repressoras , Fatores de Transcrição , Expansão das Repetições de Trinucleotídeos/genética
19.
Brain Pathol ; 15(4): 287-95, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16389941

RESUMO

Spinocerebellar ataxia type 7 (SCA7) represents a very rare and severe autosomal dominantly inherited cerebellar ataxia (ADCA). It belongs to the group of CAG-repeat or polyglutamine diseases with its underlying molecular genetical defect on chromosome 3p12-p21.1. Here, we performed a systematic study of the neuropathology on unconventional thick serial sections of the first available brain tissue of a genetically confirmed late-onset SCA7 patient with a very short CAG-repeat expansion. Along with myelin pallor of a variety of central nervous fiber tracts, we observed i) neurodegeneration in select areas of the cerebral cortex, and ii) widespread nerve cell loss in the cerebellum, thalamus, nuclei of the basal ganglia, and brainstem. In addition, upon immunocytochemical analysis using the anti-polyglutamine antibody 1C2, immunopositive neuronal intranuclear inclusions bodies (NI) were observed in all cerebellar regions, in all parts of the cerebral cortex, and in telencephalic and brainstem nuclei, irrespective of whether they underwent neurodegeneration. These novel findings provide explanations for a variety of clinical symptoms and paraclinical findings of both our and other SCA7 patients. Finally, our immunocytochemical analysis confirms previous studies which described the presence of NI in obviously degenerated brain and retinal regions as well as in apparently well-preserved brain regions and retina of SCA7 patients.


Assuntos
Encéfalo/patologia , Ataxias Espinocerebelares/patologia , Idoso , Feminino , Humanos , Imuno-Histoquímica , Degeneração Neural/patologia , Retina/patologia , Ataxias Espinocerebelares/genética , Expansão das Repetições de Trinucleotídeos
20.
Histol Histopathol ; 20(2): 429-36, 2005 04.
Artigo em Inglês | MEDLINE | ID: mdl-15736047

RESUMO

Aldose reductase is an NADPH-dependent aldo-keto reductase best known as the rate-limiting enzyme of the polyol pathway that is implicated in the complications of diabetes. Aldose reductase appears to be involved in a variety of disease states other than diabetes, presumably due to its ability to catalyze the reduction of a broad spectrum of aldehydes, including some cytotoxic products of lipid peroxidation. Although the data regarding expression of aldose reductase in normal liver are conflicting, prior studies have suggested that the enzyme may be induced in diseased liver. The goal of these studies was to characterize expression of aldose reductase in normal and diseased human liver, using RT-PCR, Western analysis and immunohistochemistry. Aldose reductase transcripts and protein were detected at low levels in control human livers. In contrast, levels of aldose reductase mRNA and protein were increased in chronically diseased human livers. Immunohistochemistry demonstrated localization of aldose reductase in sinusoidal lining cells; dual immunofluorescence confocal microscopy with the macrophage marker, CD68, confirmed that the aldose reductase-positive sinusoidal lining cells were Kupffer cells. Abundant aldose reductase-positive, CD68-positive cells were present in the fibrous septa of cirrhotic livers, accounting for the increase in immunoreactive aldose reductase in diseased livers. Immunostaining of human lung, spleen and lymph node revealed that macrophages in those tissues also express aldose reductase. These data are the first to demonstrate that aldose reductase is expressed by human macrophages in various tissues and suggest that this enzyme may play a role in immune or inflammatory processes.


Assuntos
Aldeído Redutase/metabolismo , Hepatopatias/enzimologia , Fígado/enzimologia , Aldeído Redutase/genética , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Sequência de Bases , Estudos de Casos e Controles , DNA Complementar/genética , Expressão Gênica , Humanos , Imuno-Histoquímica , Células de Kupffer/enzimologia , Células de Kupffer/patologia , Fígado/citologia , Hepatopatias/patologia , Macrófagos/enzimologia , Macrófagos/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
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