TDP-43 regulates early-phase insulin secretion via CaV1.2-mediated exocytosis in islets.

TAR DNA-binding protein 43 kDa (TDP-43), encoded by TARDBP, is an RNA-binding protein, the nuclear depletion of which is the histopathological hallmark of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder affecting both upper and lower motor neurons. Besides motor symptoms, patients with ALS often develop nonneuronal signs including glucose intolerance, but the underlying pathomechanism is still controversial, i.e., whether it is impaired insulin secretion and/or insulin resistance. Here, we showed that ALS subjects reduced early-phase insulin secretion and that the nuclear localization of TDP-43 was lost in the islets of autopsied ALS pancreas. Loss of TDP-43 inhibited exocytosis by downregulating CaV1.2 calcium channels, thereby reducing early-phase insulin secretion in a cultured ß cell line (MIN6) and ß cell-specific Tardbp knockout mice. Overexpression of CaV1.2 restored early-phase insulin secretion in Tardbp knocked-down MIN6 cells. Our findings suggest that TDP-43 regulates cellular exocytosis mediated by L-type voltage-dependent calcium channels and thus plays an important role in the early phase of insulin secretion by pancreatic islets. Thus, nuclear loss of TDP-43 is implicated in not only the selective loss of motor neurons but also in glucose intolerance due to impaired insulin secretion at an early stage of ALS.

[Cryptococcal meningoencephalitis presenting with treatable cognitive impairment and involuntary movement].

The patient is a 72-year-old Japanese woman. Seven years prior to admission, multiple nodules in her left lung were found. Bronchoscopic biopsy of the nodules did not provide a confirmative diagnosis, and probable diagnosis of cryptococcosis was made. Follow-up CT scan of the chest revealed reduction in size of the lung nodules. She was admitted to our hospital due to progressive cognitive impairment and difficulty in walking that lasted for 5 months. On admission, athetotic involuntary movement was observed in her lower extremities, predominantly in the right side. Blood and cerebrospinal fluid culture of the patient were positive for Cryptococcus neoformans. Antifungal drugs resolved the cognitive impairment, the difficulty in walking, and the involuntary movement. We assessed the cognitive impairment and observed the clinical improvement of the patient, with the use of neuropsychological examinations. To our knowledge, there has been only a few reported case of cryptococcal meningoencephalitis presenting with treatable cognitive impairment and involuntary movement.

[A case of neuromyelitis optica spectrum disorder presenting with severe orthostatic hypotension].

The patient is a 68-year-old Japanese woman. She was admitted to our hospital due to continuous hiccups and vomiting episodes for more than one week. On examinations, muscle strength in her right lower limb was slightly decreased, and pyramidal tract signs were positive bilaterally. The fluid attenuated inversion recovery imaging of the brain showed lesions in the dorsal and lateral medulla. Serum anti-aquaporin 4 antibody was positive. We then diagnosed the patient with neuromyelitis optica spectrum disorder (NMOSD). Severe orthostatic hypotension (OH) was determined. While hiccups and vomiting improved gradually, OH lasted for more than three weeks. OH improved after administration of intravenous methylpredonisolone-pulse therapy. In this case, the lesion in the dorsal medulla might be responsible for OH. We considered that OH might be one of the symptoms of NMOSD.