Screening for TARDBP mutations in Japanese familial amyotrophic lateral sclerosis.
ABSTRACT TAR-DNA-binding protein 43 (TDP-43), encoded by the TARDBP gene on chromosome 1p36.22, has been identified as the major pathological protein in abnormal inclusions in neurons and glial cells in sporadic amyotrophic lateral sclerosis (SALS), SOD1-negative familial ALS (FALS) and frontotemporal lobar dementia (FTLD). Twenty mutations of TARDBP in SOD1-negative FALS and SALS cases have been reported so far. To investigate the presence and frequency of TARDBP mutations in Japanese SOD1-negative FALS patients, we performed mutational screening of TARDBP in 30 SOD1-negative FALS patients. An N352S mutation was found in one case of FALS, but no TARDBP mutations were found in cases of SALS. It was thought that this mutation increases TDP-43 phosphorylation. This might lead to impaired nuclear cytoplasmic transport or protein-protein interaction, thereby leading to TDP-43 accumulation.
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ABSTRACT: In this case report, for the first time, we provide descriptive cliniconeuropathological features of a case of familial amyotrophic lateral sclerosis (familial ALS, FALS) with p.N352S mutation in TARDBP. The present Japanese patient (Figure 1, II-4, the proband) was born in Wakayama Prefecture. At 74 years, he experienced weakness in the muscles of both hand. He visited our neurology department with complaints of impaired fine motor skills of both hands at 76 years, and his neurological examination showed muscle weakness and muscular atrophy of both hands. At 77 years, his muscle weakness descended to both thighs, leading to difficulty in walking by himself. While his tongue revealed slight atrophy and fasciculation, there were no detectable upper motor neuron (UMN) signs, cognitive impairment, dysphagia, dysarthria, sensory disturbances, or gait disturbances. Electromyography disclosed active denervation of muscle potentials in both the upper and lower extremities, and he was diagnosed with ALS. His respiratory function gradually worsened, and he died of respiratory failure at 78 years, 4 years after onset. In the patient's pedigree, his niece (III-2), who is now 60 years old, was also affected by ALS. She had complaints of muscle weakness of the lower extremities at 45 years and is currently on ventilatory support. She can still communicate using lip movements.Neuropathology and Applied Neurobiology 10/2013; · 4.84 Impact Factor
- Neuropathology and Applied Neurobiology 12/2013; · 4.84 Impact Factor
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ABSTRACT: TDP-43 is a nuclear protein whose abnormal aggregates are implicated in ALS and FTLD. Recently, an Asn/Gln rich C-terminal segment of TDP-43 has been shown to produce aggregation in vitro and reproduce most of the protein's pathological hallmarks in cells, but little is known about this segment's structure. Here, CD and 2D heteronuclear NMR spectroscopies provide evidence that peptides corresponding to the wild type and mutated sequences of this segment adopt chiefly disordered conformations that, in the case of the wild type sequence, spontaneously forms a β-sheet rich oligomer. Moreover, MD simulation provides evidence for a structure consisting of two β-strands and a well-defined, yet non-canonical structural element. Furthermore, MD simulations of four pathological mutations (Q343R, N345K, G348V and N352S) occurring in this segment predict that all of them could affect this region's structure. In particular, the Q343R variant tends to stabilize disordered conformers, N345K permits the formation of longer, more stable β-strands, and G348V tends to shorten and destabilize them. Finally, N352S acts to alter the β-stand register and when S352 is phosphorylated, it induces partial unfolding. Our results provide a better understanding of TDP-43 aggregation process and will be useful to design effectors capable to modulate its progression.Archives of Biochemistry and Biophysics 01/2014; · 3.04 Impact Factor