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Tremor Ataxia Syndrome (tremor + ataxia_syndrome)

Distribution by Scientific Domains

Medical Sciences	50%

Selected Abstracts

RNA-mediated neurodegeneration in repeat expansion disorders

ANNALS OF NEUROLOGY, Issue 3 2010
Peter K. Todd MD
Most neurodegenerative disorders are thought to result primarily from the accumulation of misfolded proteins, which interfere with protein homeostasis in neurons. For a subset of diseases, however, noncoding regions of RNAs assume a primary toxic gain-of-function, leading to degeneration in many tissues, including the nervous system. Here we review a series of proposed mechanisms by which noncoding repeat expansions give rise to nervous system degeneration and dysfunction. These mechanisms include transcriptional alterations and the generation of antisense transcripts, sequestration of mRNA-associated protein complexes that lead to aberrant mRNA splicing and processing, and alterations in cellular processes, including activation of abnormal signaling cascades and failure of protein quality control pathways. We place these potential mechanisms in the context of known RNA-mediated disorders, including the myotonic dystrophies and fragile X tremor ataxia syndrome, and discuss recent results suggesting that mRNA toxicity may also play a role in some presumably protein-mediated neurodegenerative disorders. Lastly, we comment on recent progress in therapeutic development for these RNA-dominant diseases. ANN NEUROL 2010;67:291,300 [source]

FUS-Immunoreactive Intranuclear Inclusions in Neurodegenerative Disease

BRAIN PATHOLOGY, Issue 3 2010
John Woulfe
Abstract Neuronal intranuclear inclusions (NIIs) are a histopathological hallmark of several neurodegenerative disorders. However, the role played by NIIs in neurodegenerative pathogenesis remains enigmatic. Defining their molecular composition represents an important step in understanding the pathophysiology of these disorders. Recently, a nuclear protein, "fused-in-sarcoma" (FUS) was identified as the pathological protein in two forms of frontotemporal lobar degeneration (FTLD-IF, formerly known as neuronal intermediate filament inclusion disease, and FTLD-UPS, formerly known as atypical FTLD-U), both of which are characterized by the presence of NII. The objective of the present study was to determine the range of neurodegenerative disorders characterized by FUS-positive NIIs. Immunostaining for FUS revealed intense reactivity of NIIs in FTLD-IF and FTLD-UPS as well as in Huntington's disease, spinocerebellar ataxias 1 and 3, and neuronal intranuclear inclusion body disease. In contrast, there was no FUS staining of NIIs in inherited forms of FTLD-TDP caused by GRN and VCP mutations, fragile-X-associated tremor ataxia syndrome, or oculopharyngeal muscular dystrophy. In a cell culture model of Huntington's disease, NIIs were intensely FUS-positive. NII-bearing cells displayed loss of the normal diffuse nuclear pattern of FUS staining. This suggests that sequestration of nuclear FUS by NIIs may interfere with its normal nuclear localization. [source]

Clinical involvement in daughters of men with fragile X-associated tremor ataxia syndrome

CLINICAL GENETICS, Issue 1 2010
W Chonchaiya
Chonchaiya W, Nguyen DV, Au J, Campos L, Berry-Kravis EM, Lohse K, Mu Y, Utari A, Hervey C, Wang L, Sorensen P, Cook K, Gane L, Tassone F, Hagerman RJ. Clinical involvement in daughters of men with fragile X-associated tremor ataxia syndrome. Women with the fragile X mental retardation 1 (FMR1) premutation often have concerns about neurological and medical problems, as they become older and if their fathers experience fragile X-associated tremor/ataxia syndrome (FXTAS). We therefore determined the prevalence of these problems in 110 daughters of men with FXTAS [mean age of 44.8 years (SD 8.2)]. We compared them with 43 female controls with normal FMR1 alleles [mean age of 43.8 years (SD 8.1)] and 36 premutation carrier daughters of parents with the premutation, but without FXTAS [mean age of 43.5 years (SD 7.7)]. Overall, daughters of men with FXTAS have a higher prevalence of neurological symptoms including tremor, balance problems, memory problems, and dizziness, menopausal symptoms, and psychiatric involvement including sleep problems and anxiety when compared with non-carrier female controls. Reported balance problems and menopausal symptoms were significantly higher in daughters of men with FXTAS than in carrier daughters of parents without FXTAS, suggesting the potential influence of background gene effects. Therefore, neurological, psychological and gynecological surveillance should be warranted to better provide appropriate counseling, management and care for daughters of men with FXTAS. Biological markers of additional gene effects that predispose individuals with the premutation to FXTAS need to be developed. [source]