Hiroshi Nishimune, PhD
Anatomy and Cell Biology
Ph.D., 1997 Osaka University, Japan
Postdoctoral, IBDM, INSERM U.382, France, C.E. Henderson lab
Postdoctoral, Washington Univ. Sch. of Med., St. Louis, J.R. Sanes lab
Postdoctoral, Harvard Univ. Dept. MCB, Cambridge, J.R. Sanes lab
The nervous system plays essential roles for our daily life: movement, communicating, sensing, learning, and memory. These nervous system functions depend on the cell-cell communication at synapses. The synapses between motor neurons and skeletal muscles are called neuromuscular junctions (NMJs). Presynaptic active zones are synaptic vesicle release sites that play essential roles for synaptic transmission and pathology of NMJs (Figure 1).
Our studies show that NMJ active zones are organized via interactions between an active zone-organizer (laminin β2), a receptor for the organizer (presynaptic voltage-gated calcium channels, VGCCs), and active zone proteins (Bassoon, Piccolo, Figure 2). Recently, we have analyzed the active zone-specific proteins at NMJs using super resolution microscopy (STED), which gives resolution beyond confocal microscopy. We revealed the protein distribution patter at much higher resolution (PQ-type VGCCs) and an unexpected side-by-side pattern (Bassoon-Piccolo-Bassoon) with the STED microscope (Figure 3).
Aged rodents show NMJ degeneration and denervation; however, physical exercise is known to ameliorate NMJ denervation of aged animals. We identified a potential mechanism how exercise exert beneficial effect on NMJs. Active zones became impaired during aging; however, exercise ameliorated the active zone impairment in aged NMJs (Figure 4). We aim to elucidate molecular mechanisms that are activated by exercise to come up with therapeutic strategies to maintain aged NMJs.
In ALS patients and animal models, NMJs degenerate prior to the degeneration of motor neuron cell bodies, which causes NMJ denervation and dying-back neuropathy. The mechanisms of NMJ denervation and the reasons for the preferential death of motor neurons in ALS remain unknown; therefore, effective treatments for ALS patients are lacking. Accumulation of degenerated mitochondria and defect in mitophagy (mechanism to reduce degenerated mitochondria by autophagy) at NMJs seem to play roles in NMJ denervation in ALS model mice (Figure 5). In addition, we developed software to analyze mouse behavior in their home cage (Figure 6, "Mouse Behavior Tracker"). Together, we aim to elucidate the molecular mechanisms underlying NMJ denervation in ALS and to identify new therapeutic targets.
Hiroshi Nishimune, PhD
Yomna Badawi, PhD
Takashi Matsuda, M.D., Ph.D.
Kazushi Okada, PhD.
Former Lab Members
- Takafumi Mizushige, PhD (Post Doc): Associate Professor Department of Applied Biological Chemistry, Faculty of Agriculture, Utsunomiya University
- Sara Billings, MS (Grad student): Research Assistant, Stanford School of Medicine
- Jie Chen, MD PhD (Post Doc): Residency, the Neuropathology fellowship, Washington University in St. Louis.
- Gwenaelle Clarke, PhD (Post Doc): Private Corporation
- Lisa Nadeau, DO (Research Asst): Residency, Anesthesia, St Louis University
- Tomohiro Tanaka, PhD (Post Doc): Postdoctoral fellow, Scripps Research Institute
- Kellen Wright (K-INBRE summer fellow): University of Kansas Lawrence, Undergraduate program
- Robert Rogers, PhD (Post Doc): Assistant Professor, Kansas City University of Medicine and Biosciences
- Sudheer Tungtur, MS (Research Associate): Research technician, University of Minnesota
- University of Kansas Neuromuscular Research Division
- Midwest Stem Cell Therapy Center
- Kansas Intellectual and Developmental Disabilities Research Center
- Institute for Neurological Discoveries