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1.
J R Soc Interface ; 17(162): 20190775, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31910770

RESUMEN

Human proteins have not been reported to survive in free nature, at ambient temperature, for long periods. Particularly, the human brain rapidly dissolves after death due to auto-proteolysis and putrefaction. The here presented discovery of 2600-year-old brain proteins from a radiocarbon dated human brain provides new evidence for extraordinary long-term stability of non-amyloid protein aggregates. Immunoelectron microscopy confirmed the preservation of neurocytoarchitecture in the ancient brain, which appeared shrunken and compact compared to a modern brain. Resolution of intermediate filaments (IFs) from protein aggregates took 2-12 months. Immunoassays on micro-dissected brain tissue homogenates revealed the preservation of the known protein topography for grey and white matter for type III (glial fibrillary acidic protein, GFAP) and IV (neurofilaments, Nfs) IFs. Mass spectrometry data could be matched to a number of peptide sequences, notably for GFAP and Nfs. Preserved immunogenicity of the prehistoric human brain proteins was demonstrated by antibody generation (GFAP, Nfs, myelin basic protein). Unlike brain proteins, DNA was of poor quality preventing reliable sequencing. These long-term data from a unique ancient human brain demonstrate that aggregate formation permits for the preservation of brain proteins for millennia.


Asunto(s)
Encéfalo , Agregado de Proteínas , Secuencia de Aminoácidos , Encéfalo/metabolismo , Proteína Ácida Fibrilar de la Glía/metabolismo , Humanos
2.
J Neurol Neurosurg Psychiatry ; 78(11): 1267-70, 2007 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-17578852

RESUMEN

Giant axonal neuropathy (GAN; MIM 256850) is a severe childhood onset autosomal recessive sensorimotor neuropathy affecting both the peripheral nerves and the central nervous system. Bomont and colleagues identified a novel ubiquitously expressed gene they named Gigaxonin on chromosome 16q24 as the cause of GAN in a number of families. We analysed five families with GAN for mutations in the Gigaxonin gene and mutations were found in four families; three families had homozygous mutations, one had two compound heterozygous mutations and one family had no mutation identified. All families had the typical clinical features, kinky hair and nerve biopsy. We report some unusual clinical features associated with GAN and Gigaxonin mutations as well as confirm the heterogeneity in GAN and the identification of two families with manifesting carriers.


Asunto(s)
Axones , Proteínas del Citoesqueleto/genética , Análisis Mutacional de ADN , Tamización de Portadores Genéticos , Genotipo , Enfermedades del Sistema Nervioso/genética , Fenotipo , Adolescente , Adulto , Axones/patología , Biopsia , Encéfalo/patología , Niño , Preescolar , Aberraciones Cromosómicas , Cromosomas Humanos Par 16 , Femenino , Genes Recesivos/genética , Homocigoto , Humanos , Masculino , Microscopía Electrónica , Fibras Nerviosas Mielínicas/patología , Enfermedades del Sistema Nervioso/diagnóstico , Examen Neurológico , Nervio Sural/patología
3.
Brain ; 129(Pt 2): 411-25, 2006 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-16364956

RESUMEN

Hereditary sensory and autonomic neuropathy type I (HSAN I) is the most frequent type of hereditary neuropathy that primarily affects sensory neurons. The genetic locus for HSAN I has been mapped to chromosome 9q22.1-22.3 and recently the gene was identified as SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1. Sequencing in HSAN I families have previously identified mutations in exons 5, 6 and 13 of this gene. We analysed the SPTLC1 gene for mutations in 8 families with HSAN I, 60 individuals with sporadic sensory neuropathy, 6 HSAN II families, 20 Charcot-Marie-Tooth type I families and 20 families with Charcot-Marie-Tooth type II. Six HSAN I families and a single sporadic neuropathy case had an identical SPTLC1 mutation. No mutations were found in the other groups. Genetic haplotyping across the HSAN I critical region in 5 families and the sporadic case suggested a common founder. Several characteristics, previously not widely recognized were identified, including lack of penetrance of the SPTLC1 mutation in some individuals, variability in age of onset along with an earlier age of onset in younger generations, in some patients surprisingly early and often severe motor involvement and an earlier onset characterized by motor involvement with demyelinating features in males compared to females in 4 families. The sensory findings were often disassociated with prominent pain and temperature loss. Neurophysiology mainly showed a sensory axonal neuropathy but in many individuals there was electrical evidence of demyelination. Sural nerve biopsies from six affected individuals and the post-mortem findings in 1 case showed mainly axonal loss. This in depth study on the phenotype of HSAN I in 6 families and a single sporadic case with a common founder identifies a number of poorly recognized features in this disorder and highlights the clinical heterogeneity both within and between families suggesting the influence of other genetic and acquired factors.


Asunto(s)
Aciltransferasas/genética , Neuropatías Hereditarias Sensoriales y Autónomas/diagnóstico , Adulto , Edad de Inicio , Anciano , Axones/patología , Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/patología , Análisis Mutacional de ADN , Electrofisiología , Femenino , Haplotipos , Neuropatías Hereditarias Sensoriales y Autónomas/genética , Neuropatías Hereditarias Sensoriales y Autónomas/patología , Humanos , Masculino , Persona de Mediana Edad , Conducción Nerviosa , Neuronas Aferentes , Linaje , Penetrancia , Serina C-Palmitoiltransferasa , Factores Sexuales , Nervio Sural/patología
6.
Exp Neurol ; 213(2): 326-35, 2008 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-18619438

RESUMEN

AIMS: Axonal pathology extends to the axonal cytoarchitecture leaving its signature on axoskeletal proteins. This study investigated whether neurofilament (NfH) phosphorylation would relate to the dynamics of axonal pathology in multiple sclerosis (MS). METHODS: NfH phosphoforms (SMI32, SMI34, SMI35) were quantified by ELISA from microdissected samples of control and MS brain and spinal cord. Individual axons were analysed by electron microscopy, densitometrically and morphologically in adjacent tissue sections. Experiments were carried out pre- and post enzymatic dephosphorylation. RESULTS: In control tissue a rostro-caudal gradient of NfH indicated an increase in axonal density from the brain gray matter towards the spinal cord. The highest levels of phosphorylated and hyperphosphorylated NfH were found in acute lesions of brain and spinal cord, in contrast to chronic lesions where levels were lower than in white matter, consistent with axonal loss. Dephosphorylated NfH was higher, but less densly packed in MS white matter axons compared to control tissue. CONCLUSIONS: The findings suggest that a less organised/compact axoskeleton or impaired axonal transport may represent an early sign of axonal pathology within the normal appearing white matter in MS. Subsequently a proportional increase of dephosphorylated NfH, aberrant phosphorylation and/or aggregation may occur whilst the protein is transported through the white matter towards the MS plaque, where hyperphosphorylated NfH dominates.


Asunto(s)
Axones/metabolismo , Axones/patología , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/patología , Proteínas de Neurofilamentos/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Axones/química , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas de Neurofilamentos/análisis , Fosforilación , Isoformas de Proteínas/análisis , Isoformas de Proteínas/metabolismo
7.
Br J Haematol ; 117(3): 541-5, 2002 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-12028020

RESUMEN

An autoimmune mechanism in the pathogenesis of myelodysplastic syndrome (MDS) is suggested by response to immunosuppression, with CD8+ T-lymphocytes implicated in the haematopoietic suppression. We therefore sought evidence for human leucocyte antigen (HLA) restriction and variant frequency differences in selected polymorphisms at the loci for the immunomodulatory cytokines, tumour necrosis factor alpha (TNF-alpha), lymphotoxin-alpha (LT-alpha) and interleukin 10 (IL-10) in patients with MDS and acute myeloid leukaemia (AML) compared with normal controls. DNA from 150 MDS/AML patients [24 AML, 53 refractory anaemia (RA), 25 RA with excess blasts (RAEB), four RAEB in transformation (RAEBt), 21 sideroblastic leukaemia, 22 chronic myelomonocytic leukaemia] was screened. Control data was from Scottish blood donors (HLA class I/II), healthy General Practitioner-based subjects (TNF-alpha/LT-alpha) and published values (IL-10). HLA class I/II haplotypes were determined using sequence-specific primers. Polymorphisms were assayed at TNF-alpha -308, LT-alpha +252 and IL10 -824, -597 and -1082 loci. Variant frequencies of common haplotypes at HLA class I and II, high-/low-producer TNF-alpha/LT-alpha and IL-10 loci were not different between patients and controls or within the French-American-British, International Prognostic Scoring System or cytogenetic subgroups and were not associated with altered survival for MDS/AML patients. TNF2 allele frequency was greater in the MDS/AML cohort (chi2 = 6.593, P < 0.05) but the biological significance was uncertain in the absence of an increased high-producer TNF-alpha/LT-alpha haplotype frequency. We can find no genetic influence for these polymorphisms in HLA class I/II, TNF-alpha/LT-alpha and IL-10 loci on either predisposition or disease progression in MDS/AML.


Asunto(s)
Enfermedades Autoinmunes/inmunología , Citocinas/genética , Antígenos HLA/genética , Haplotipos , Síndromes Mielodisplásicos/inmunología , Enfermedad Aguda , Alelos , Enfermedades Autoinmunes/genética , Genotipo , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase II/genética , Prueba de Histocompatibilidad , Humanos , Interleucina-10/genética , Leucemia Mieloide/genética , Leucemia Mieloide/inmunología , Síndromes Mielodisplásicos/genética , Tasa de Supervivencia , Factor de Necrosis Tumoral alfa/genética
8.
J Peripher Nerv Syst ; 8(2): 100-7, 2003 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-12795714

RESUMEN

Microvasculitis may play a greater part in the pathogenesis of paraproteinaemic neuropathies than is generally recognised, producing tissue destruction by convergent immune and physical mechanisms. We present a patient with a clinical syndrome of mononeuritis multiplex and a circulating IgM lambda paraprotein, in whom bone marrow aspiration revealed a lymphoplasmacytoid lymphoma. Microvasculitic changes were present in the first nerve biopsy, and the second showed extensive destruction of neural architecture and deposition of IgM-related material. A 2-stage pathogenic cascade is postulated and explored with a review of the relevant literature.


Asunto(s)
Linfoma de Células B/complicaciones , Paraproteinemias/complicaciones , Polineuropatías/complicaciones , Vasculitis/etiología , Anciano , Complejo CD3/metabolismo , Técnicas Electrofisiológicas Cardíacas/métodos , Endotelio/ultraestructura , Fascia , Humanos , Inmunoglobulina M/metabolismo , Linfoma de Células B/metabolismo , Masculino , Microcirculación/ultraestructura , Microscopía Electrónica , Mononeuropatías/etiología , Conducción Nerviosa , Paraproteinemias/metabolismo , Paraproteínas/metabolismo , Polineuropatías/metabolismo , Literatura de Revisión como Asunto
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