Two German kindreds with familial amyotrophic lateral sclerosis due to TARDBP mutations.

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.

TDP-43-positive white matter pathology in frontotemporal lobar degeneration with ubiquitin-positive inclusions.

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.

Novel G335V mutation in the tau gene associated with early onset familial frontotemporal dementia.

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.