Neurogenetics, Molecular mechanisms of neuromuscular transmission

1977-1983

Nagoya University School of Medicine, Japan

1983-1985

Internship in Internal Medicine, Nagoya National Hospital, Japan

1985-1988

Residency and Staff in Neurology, Nagoya National Hospital, Japan

1988-1992

Nagoya University Graduate School of Medicine, Japan

1992-1993

JSPS (Japanese Society for Promotion of Science) Research Fellow,
Department of Biomedical Chemistry, Nagoya University School of Medicine, Japan

1993-1995

Research Fellow, Department of Neurology, Mayo Clinic, USA

1996-1998

Research Associate, Department of Neurology, Mayo Clinic, USA

1998-2004

Assistant Professor, Mayo Medical School, USA

2004-present

Professor, Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Japan

Pathomechanisms and regulations of neuromuscular transmission defects

The neuromuscular junction is a prototypical synapse, and most synaptic molecules have been initially identified at the neuromuscular junction. Congenital defects of the neuromuscular transmission cause congenital myasthenic syndromes that are characterized by amyotrophy, muscle weakness, easy fatigability, and congenital minor anomalies. We have been working on identification of defective molecules and consequences of the defects on RNA metabolisms, protein functions, and cellular functions. We have identified molecular defects of (i) muscle nicotinic acetylcholine receptor that generates endplate potentials in response to acetylcholine released from the nerve terminal, (ii) collagen Q that anchors acetylcholinesterase to synaptic basal lamina, (iii) choline acetyltransferase that resynthesize acetylcholine at the nerve terminal, (iv) rapsyn that clusters acetylcholine receptor at the endplate, and (v) voltage-gated sodium channel that senses endplate potentials and expands depolarization signals. In most of these molecules, we exploited mutations identified in patients to disclose physiological roles and functional domains of the molecules expressed at the neuromuscular junction.

In the course of analysis of molecular mechanisms of collagen Q deficiency, we found that collagen Q inherently has a tissue-targeting signal. Collagen Q is an extracellular matrix protein and is excreted from skeletal muscles. In the current project, we will exploit the tissue-targeting signal of collagen Q to treat mice deficient for the collagen Q gene. We expect that collagen Q expressed in a limited number of muscle or other cells is excreted to extracellular space and is anchored to remote synaptic basal lamina. We have obtained promising preliminary data. We will also work on inducible pluripotent stem cells to induce the collagen Q gene ex vivo.

Congenital myasthenic syndromes are monogeneic disorders caused by dominant or recessive mutations. Some mutations unexpectedly disrupt splicing cis-elements and cause aberrant splicings. In the current projects, we will identify and characterize splicing cis-elements and their splicing trans-factors in genes expressed at the neuromuscular junction. We will expand our RNA research to other neurological diseases including myotonic dystrophy.

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21. Ohno K. Congenital myasthenic syndrome caused by prolonged acetylcholine receptor channel openings due to a mutation in the M2 domain of the epsilon subunit. Proc. Natl. Acad. Sci. USA. 92: 758-762 (1995)
22. Sine SM et al. Mutation of the acetylcholine receptor alpha subunit causes a slow-channel myasthenic syndrome by enhancing agonist binding affinity. Neuron 15: 229-239 (1995)

1995 Neurology Research Award, Mayo Clinic