RESUMEN
BACKGROUND: Abnormal neuronal inclusions composed of the transactivation response DNA-binding protein 43 (TDP-43) are characteristic neuropathologic lesions in sporadic and familial forms of amyotrophic lateral sclerosis (ALS). This makes TARDBP, the gene encoding for TDP-43, a candidate for genetic screening in ALS. OBJECTIVES: To investigate the presence and frequency of TARDBP mutations in ALS. DESIGN: Genetic analysis. SETTING: Academic research. PARTICIPANTS: One hundred thirty-four patients with sporadic ALS, 31 patients with familial non-superoxide dismutase 1 gene (non-SOD1) (OMIM 147450) ALS, and 400 healthy control subjects. MAIN OUTCOME MEASURES: We identified 2 missense mutations (G348C and the novel N352S) in TARDBP in 2 small kindreds with a hereditary form of ALS with early spinal onset resulting in fatal respiratory insufficiency without clinical relevant bulbar symptoms or signs of cognitive impairment. RESULTS: The mutations located in the C-terminus of TDP-43 were absent in 400 controls of white race/ethnicity. The novel identified N352S mutation is predicted to increase TDP-43 phosphorylation, while the G348C mutation might interfere with normal TDP-43 function by forming intermolecular disulfide bridges. CONCLUSIONS: Mutations in TARDBP are a rare cause of familial non-SOD1 ALS. The identification of TARDBP mutations provides strong evidence for a direct link between TDP-43 dysfunction and neurodegeneration in ALS.
Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Proteínas de Unión al ADN/genética , Mutación Missense/genética , Anciano , Secuencia de Aminoácidos , Esclerosis Amiotrófica Lateral/patología , Femenino , Alemania , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , LinajeRESUMEN
TDP-43 was recently identified as the major disease protein in neuronal inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). TDP-43 is not only linked to disease mechanisms in FTLD-U, but it is also the most robust marker for the specific detection of neuronal inclusions in FTLD-U. In this study, we describe additional TDP-43 pathology in the white matter as a characteristic feature in a series of 38 FTLD-U cases including 3 cases with mutations in the progranulin gene. White matter pathology was most abundant in frontal and temporal lobes, but it was also detectable in brainstem and spinal cord. Based on morphology and double-labeling experiments, white matter cells with TDP-43-positive inclusions most likely represent oligodendrocytes. Biochemically, hyperphosphorylated and truncated TDP-43 was detectable in insoluble brain extracts from affected white matter regions in FTLD-U, similar to the biochemical signature observed in FTLD-U gray matter. Taken together, these results expand the spectrum of TDP-43 pathology in FTLD-U, suggesting that white matter pathology might contribute to the neurodegenerative process and clinical symptoms in FTLD-U.
Asunto(s)
Proteínas de Unión al ADN/metabolismo , Demencia/metabolismo , Demencia/patología , Cuerpos de Inclusión/metabolismo , Ubiquitina/metabolismo , Adulto , Anciano , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Femenino , Lóbulo Frontal/metabolismo , Lóbulo Frontal/patología , Proteína Ácida Fibrilar de la Glía/metabolismo , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Lóbulo Temporal/metabolismo , Lóbulo Temporal/patologíaRESUMEN
Mutations in the tau gene cause familial frontotemporal dementia and parkinsonism linked to chromosome 17. Here we describe a novel missense mutation in exon 12 of the tau gene, G335V, in a German family with frontotemporal dementia of early age at onset, in the third decade of life. Functional analysis of recombinant tau protein with the G335V mutation showed a dramatically reduced ability to promote microtubule assembly and a more rapid and accelerated tau filament formation, suggesting that the primary effect of the mutation might be the provision of a pool of unbound tau making it available for aberrant tau aggregation.