Transactivation response (TAR) DNA-binding protein of Mr 43 kDa (TDP-43) is a major component of the tau-negative and ubiquitin-positive inclusions that characterize amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration which is now referred to as FTLD-TDP. Concurrent TDP-43 pathology has been reported in a variety of other neurodegenerative disorders such as Alzheimer's disease, forming a group of TDP-43 proteinopathy. Accumulated TDP-43 is characterized by phosphorylation and fragmentation. There is a close relationship between the pathological subtypes of FTLD-TDP and the immunoblot pattern of the C-terminal fragments of phosphorylated TDP-43. These results suggest that proteolytic processing of accumulated TDP-43 may play an important role for the pathological process. In cultured cells, transfected C-terminal fragments of TDP-43 are more prone to form aggregates than full-length TDP-43. Transfecting the C-terminal fragment of TDP-43 harboring pathogenic mutations of TDP-43 gene identified in familial and sporadic ALS cases into cells enhanced the aggregate formation. Furthermore, we found that methylene blue and dimebon inhibit aggregation of TDP-43 in these cellular models. Understanding the mechanism of phosphorylation and truncation of TDP-43 and aggregate formation may be crucial for clarifying the pathogenesis of TDP-43 proteinopathy and for developing useful therapeutics.

Mutations in the fused in sarcoma (FUS) gene are linked to a form of familial amyotrophic lateral sclerosis (ALS), ALS6. The FUS protein is a major component of the ubiquitin-positive neuronal cytoplasmic inclusions in both ALS6 and some rare forms of frontotemporal lobar degeneration (FTLD). The latter are now collectively referred to as FTLD-FUS. In the present study, we investigated the localization of FUS in human and mouse brains. FUS was detected by western blot as an approximately 72 kDa protein in both human and mouse brains. Immunohistochemistry using lightly fixed tissue sections of human and mouse brains revealed FUS-positive granular staining in the neuropil, in addition to nuclear staining. Such granules are abundant in the gray matter of the brainstem and spinal cord. They are not frequent in the telencephalon. At the light microscopic level, FUS-positive granules are often co-localized with synaptophysin and present in association with microtubule-associated protein 2-positive dendrites. In the synaptosomal fraction of mouse brain, FUS is detected mainly in the post-synaptic density fraction. Thus, while FUS is primarily a nuclear protein, it may also play a role in dendrites. In the brains of patients with FTLD with TDP-43 deposition (FTLD-TDP), the number of FUS-positive granules in the cortex is increased compared with control cases. The increase in Alzheimer's disease (AD) is less remarkable but still significant. The dendritic localization of FUS and its increase in FTLD-TDP and AD may have some implication for the pathophysiology of neurodegenerative diseases.

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Basophilic inclusions (BIs) are pathological features of a subset of frontotemporal lobar degeneration disorders, including sporadic amyotrophic lateral sclerosis (ALS) and familial ALS (FALS). Mutations in the fused in sarcoma/translocated in liposarcoma (FUS/TLS) gene have recently been identified as a cause of FALS. The FUS/TLS-immunoreactive inclusions are consistently found in cases of frontotemporal lobar degeneration with BIs; however, the association between ALS cases with BIs and FUS/TLS accumulation is not well understood. We used immunohistochemistry to analyze 3 autopsy cases of FALS with the FUS/TLS mutation and with BIs using anti-FUS/TLS antibodies. The disease durations were 1, 3, and 9 years. As the disease duration becomes longer, there were broader distributions of neuronal and glial FUS/TLS-immunoreactive inclusions. As early as 1 year after the onset, BIs, neuronal cytoplasmic inclusions and glial cytoplasmic inclusions were found in the substantia nigra in addition to the anterior horn of the spinal cord. Glial cytoplasmic inclusions are found earlier and in a wider distribution than neuronal cytoplasmic inclusions. The distribution of FUS/TLS-immunoreactive inclusions in FUS/TLS-mutated FALS with BIs was broader than that of BIs alone, suggesting that the pathogenetic mechanism may have originated from the FUS/TLS proteinopathy.

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Choreoathetoid involuntary movements are rarely reported in patients with frontotemporal lobar degeneration (FTLD), suggesting their exclusion as a supportive feature in clinical diagnostic criteria for FTLD. Here, we identified three cases of the behavioral variant of frontotemporal dementia (bvFTD) that display chorea with fused in sarcoma (FUS)-positive inclusions (FTLD-FUS) and the basophilic inclusion body disease (BIBD) subtype. We determined the behavioral and cognitive features in this group that were distinct from other FTLD-FUS cases. We also reviewed the clinical records of 72 FTLD cases, and clarified additional clinical features that are predictive of the BIBD pathology. Symptom onset in the three patients with chorea was at 44.0 years of age (±12.0 years), and occurred in the absence of a family history of dementia. The cases were consistent with a clinical form of FTD known as bvFTD, as well as reduced neurological muscle tone in addition to chorea. The three patients showed no or mild parkinsonism, which by contrast, increased substantially in the other FTLD cases until a later stage of disease. The three patients exhibited severe caudate atrophy, which has previously been reported as a histological feature distinguishing FTLD-FUS from FTLD-tau or FTLD-TAR DNA-binding protein 43. Thus, our findings suggest that the clinical feature of choreoathetosis in bvFTD might be associated with FTLD-FUS, and in particular, with the BIBD subtype.

A 75-year-old man was admitted to our hospital because of parkinsonism. Past history included recurrent nasal hemorrhage since around 12 years of age. His father also had recurrent nasal hemorrhage. On admission, he had telangiectasia on the forehead. The routine serum chemistry and complete blood count were unremarkable including liver function tests and hepatitis screening tests. T1-weighted image (T1WI) of brain MRI revealed bilateral hyperintensities involving the substantia nigra and the globus pallidus ( Fig. 1). Arterial-phase image of abdominal enhanced CT revealed multiple abnormal vessels throughout the liver. Early filling of right hepatic vein suggested presence of arteriovenous shunts (Fig. 2). The serum ammonia level was 126 g/dl (normal 12-66 g/dl) and the whole blood manganese level was 4.1 g/dl (normal 0.8-2.5 g/dl). He was diagnosed as hereditary hemorrhagic telangiectasia (HTT). There are only two reports which include the brain MRI of HTT with hepatic involvement (1, 2). We considered the hyperintensities on T1WI to be caused by deposition of manganese due to the intrahepatic arteriovenous shunts.