Main Research Areas

Prion diseases including Creutzfeldt-Jakob disease in humans and bovine spongiform encephalopathy (BSE) in cattles are caused by prions, which mainly consist of the disease-associated amyloidogenic prion protein, designated PrPSc. Once prions invade the body, PrPSc is believed to associate with the normal PrP (PrPC) expressed on the cell surface of neurons and change conformation of the PrPC into that of PrPSc, resulting in marked amplification of PrPSc or propagation of prions in the brains (Figure 1). We and others showed that mice devoid of PrPC neither developed the disease nor propagated prions after intracerebral inoculation of prions, clearly indicating that conversion of PrPC into PrPSc is essential for the pathogenesis of the diseases. However, the molecular pathogenesis of prion diseases remains largely unknown.

Research Projects

●	Understand the molecular mechanisms of prion diseases by investigating the normal function of PrPC and the neurotoxicity of PrPSc.
	We showed that mice devoid of PrPC is vulnerable to brain ischemia, developing marked apoptosis of hippocampal neurons, compared to wild-type mice. Moreover, we identified the first homologue molecule of PrP, termed PrP-like protein (PrPLP)/Doppel (Dpl). PrPLP/Dpl is neurotoxic causing Purkinje cell degeneration in mice whereas PrPC functionally antagonizes the neurotoxicity of PrPLP/Dpl, rescuing the mice from Purkinje cell degeneration (Figure 2). We are now investigating such neuroprotective functions of PrPC at the molecular levels. We also elucidate the neurotoxic mechanisms of PrPSc.
●	Develop therapeutics and vaccines against prion diseases.
	We showed that immunization with heterologous bovine and sheep recombinant PrPs could overcome the immune tolerance to PrP in mice, eliciting considerably high titers of anti-PrP autoantibodies, and exhibited prophylactic effectiveness against a mouse-adapted prion in mice, prolonging incubation times in the immunized mice compared to non-immunized mice. We are now interesting in more powerful molecules, which could elicit more strong protective immunity against the diseases. We are also developing immunotherapeutic against the diseases.
●	Develop highly sensitive methods for early diagnosis of prion diseases.
	Prion diseases are clinically asymptomatic for a long period, ranging from years to several tens of years, and asymptomatic individuals are unable to be diagnosed because no sensitive diagnostic methods are currently available. Importantly, these latently infected individuals are potential sources for secondary transmission of the diseases among human populations. Therefore, to prevent such a transmission of the diseases, development of highly sensitive diagnostic methods of prion diseases is urgently awaited with great anticipation.

Supervisors

	Professor Suehiro SAKAGUCHI TEL: 088-633-7438 E-mail: sakaguch@ier.tokushima-u.ac.jp
	Associate Professor Isao INOUE TEL: 088-633-7441 E-mail: iinoue@ier.tokushima-u.ac.jp
	Assistant Professor Yoshitaka YAMAGUCHI TEL: 088-633-9256 E-mail: y-yama@ier.tokushima-u.ac.jp
	Assistant Professor Tsuyoshi MORI TEL: 088-633-7439 E-mail: morit@ier.tokushima-u.ac.jp

WANTED

We are now seeking graduate students who are interested in our projects. Do not hesitate to contact me.
Tel: +81-88-633-7438, Fax: +81-88-633-7440,
E-mail: sakaguch@ier.tokushima-u.ac.jp

Publications