transforming-growth-factor-beta and Leukoencephalopathy--Progressive-Multifocal

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a single-gene disorder directly affecting the cerebral small blood vessels, that is caused by mutations in the HTRA1 gene encoding HtrA serine peptidase/protease 1 (HTRA1). CARASIL is the second known genetic form of ischemic, nonhypertensive, cerebral small-vessel diseases with an identified gene, following CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). The exact prevalence of CARASIL is currently unknown, and so far about 50 patients have been reported, most of them from Japan and two from China. Genetically no founder haplotype has been identified, and so the disease is expected to be found more widely. The main clinical manifestations are ischemic stroke or stepwise deterioration in brain functions, progressive dementia, premature baldness, and attacks of severe low back pain or spondylosis deformans/disk herniation. The most characteristic brain MRI findings are homogeneously confluent white-matter changes and multiple lacunar infarctions in the basal ganglia and thalamus. Histopathologically, CARASIL is characterized by intense arteriosclerosis, mainly in the small penetrating arteries, without granular osmiophilic materials (GOM) or amyloid deposition. CARASIL is a prototype single-gene disorder of cerebral small vessels, secondary to and distinct from CADASIL. CARASIL-associated mutant HTRA1s exhibited decreased protease activity and failed to repress transforming growth factor-β (TGF-β) family signaling, indicating that the increased TGF-β signaling causes arteriopathy in CARASIL. Therefore, HTRA1 represents another new gene to be considered in future studies of the mechanisms and therapeutic strategies of cerebral small-vessel diseases, as well as alopecia and degenerative vertebral/disk diseases.

Topics: Adult; Alopecia; Blood Vessels; Brain; Cerebral Infarction; Dementia, Vascular; Genes, Recessive; High-Temperature Requirement A Serine Peptidase 1; Humans; Leukoencephalopathy, Progressive Multifocal; Low Back Pain; Male; Middle Aged; Mutation; Serine Endopeptidases; Spondylosis; Syndrome; Transforming Growth Factor beta

Topics: Adult; Cerebral Infarction; Dementia, Vascular; Female; Genes, Recessive; High-Temperature Requirement A Serine Peptidase 1; Humans; Leukoencephalopathy, Progressive Multifocal; Male; Serine Endopeptidases; Transforming Growth Factor beta

Progressive multifocal leukoencephalopathy is a fatal demyelinating disease of the central nervous system frequently seen in patients with impaired immune systems, particularly acquired immunodeficiency syndrome. JC virus (JCV), a human neurotropic polyomavirus, is the etiologic infectious agent of this disease.. The significantly higher incidence of progressive multifocal leukoencephalopathy in patients with acquired immunodeficiency syndrome than in patients with other immunosuppressive conditions suggests that molecular interactions between human immunodeficiency virus 1 and JCV, via the Tat protein, are responsible for the activation of the JCV enhancer/promoter and the development of progressive multifocal leukoencephalopathy. An indirect mechanism through activation of cytokines, such as transforming growth factor beta1 and Smads 3 and 4, may also be responsible for the enhancement of JCV gene expression.. Immunohistochemical analysis in progressive multifocal leukoencephalopathy samples and chloramphenicol acetyl transferase assays on cell cultures were performed to corroborate this hypothesis.. The JCV capsid protein VP-1 was found in the nuclei of oligodendrocytes and in the nuclei and cytoplasm of bizarre astrocytes. Human immunodeficiency virus proteins, including p24 and Tat, were detected in the cytoplasm of astrocytes. Tat, but not p24, was detected in oligodendrocytes, suggesting that extracellular Tat accumulates in the nuclei of oligodendrocytes, where JCV gene transcription takes place. High levels of transforming growth factor beta1 and Smads 3 and 4 were detected in JCV-infected oligodendrocytes. Results from in vitro studies confirm activation of the JCV early and late promoters by Smads 3 and 4.. These observations support our model, suggesting that the induction of transforming growth factor beta1 by human immunodeficiency virus 1 Tat can stimulate its downstream factors, including Smads 3 and 4, which in turn augment transcription of the JCV promoter in glial cells.

Topics: Adult; Aged; Astrocytes; Brain; DNA-Binding Proteins; DNA, Viral; Female; Gene Expression Regulation, Viral; HIV Infections; HIV-1; Humans; Immunohistochemistry; JC Virus; Leukoencephalopathy, Progressive Multifocal; Male; Middle Aged; Oligodendroglia; Signal Transduction; Smad3 Protein; Smad4 Protein; Trans-Activators; Transcriptional Activation; Transforming Growth Factor beta; Transforming Growth Factor beta1; Viral Proteins