Division of Molecular Neurobiology

Main Research AreasResearch ProjectsMember

 

Main Research Areas

Markedly different from other neurodegenerative diseases, prion diseases are a group of infectious neurodegenerative disorders. Interestingly, the causative agents, prions, are made of a protein that is encoded on host genome. We are conducting research projects described below in order to abolish the diseases on the world by revealing the mechanisms underlying prion replication and degenerative neuronal cell death.

 

  • Researches on physiological functions of prion protein that constitutes a prion.
  • Researches on the mechanism underlying prion replication.
  • Researches on the mechanism underlying degenerative neuronal cell death induced by prions.
  • Researches on preventative and therapeutic developments against prion diseases.

 

Research Projects

1.What is a mechanism of prion replication?

Prions are produced by conformational changes of the normal prion protein, which is expressed in the brain, in particularly by neurons, as a glycoprotein anchored to the cell membrane via a glycosyl-phosphatidyl-inositol moiety, to the abnormal prion protein (Figure 1). However, the mechanism of the structural changes of prion protein remains unknown. We are investigating the molecular mechanism using prion-infected mouse neuroblastoma N2a cells and genetically engineered knockout and transgenic mice.

 

Figure 1: Molecular Pathogenesis of Prion
Figure 1: Molecular Pathogenesis of Prion

2.What is the function of normal prion protein?

We are investigating the physiological functions of the normal prion protein using mice genetically engineered knockout and transgenic for prion protein. We also identified a new molecule named Dpl, a homologue molecule of prion protein. Interestingly, these two molecules are functionally antagonized to each other. Dpl exerts a neurotoxic activity in the absence of prion protein, inducing cerebellar Purkinje neuron death, whereas prion protein rescues the neurons by inhibiting the neurotoxicity of Dpl (Figure 2). We further showed that prion protein could rescue hippocampal neurons from ischemic damages. It is thus suggested that prion protein is involved in neuroprotective functions. However, the molecular mechanism remains unknown. It is highly expected that investigation of the mechanism underlying the neuroprotective function of prion protein could lead to understanding of the mechanism for neuronal cell death in prion diseases.

 

Figure 2: Purkinje cell degeneration
Figure 2: Purkinje cell degeneration

Immunohistochemical Purkinje cell staining by anti-calbindin antibody

3.What is a mechanism of neuronal cell death in prion diseases?

As described above, prions are produced by conformational changes of the normal prion protein to the abnormal prion protein. Indeed, we have shown that mice knockout for the normal prion protein are resistant to the diseases even after intracerebral inoculation with prion. This result indicates that the conversion of the normal prion protein into the abnormal prion protein is necessary for neuronal cell death in prion diseases. The prion production results in accumulation of the abnormal prion protein in the brain. It is thus believed that the accumulation of the abnormal prion protein may be involved in the neuronal cell death in prion diseases. However, the molecular mechanism underlying the neuronal cell death induced by the abnormal prion protein remains unknown. We are now investigating the mechanism.

4.How can we prevent and treat prion diseases?

Is it possible to develop prion vaccines? Exogenous pathogens such as influenza virus are recognized as non-self objects and then destroyed by host immune system because they are made of their own molecules that are not encoded on host genome but encoded on their genome. It is therefore possible to develop vaccines against exogenous pathogens. However, prions are made of the host-encoded prion protein, meaning that prions are unable to be recognized and abolished by the immune system. Thus, it seems very difficult to develop prion vaccines. However, the abnormal prion protein constituting prions is different in protein structures from the normal prion protein. If we can successfully induce immunological responses against these different structures of the abnormal prion protein or prions, prion can be eliminated. We are now challenging these kinds of prion vaccines. Furthermore, we are conducting researches on therapeutics against prion diseases.

5.Others

Please propose projects related to prion diseases and contact us. Any projects will be seriously considered.

 

Member

Professor Suehiro SAKAGUCHIProfessor
Suehiro SAKAGUCHI
TEL : 088-633-7438
E-mail : sakaguch@ier.tokushima-u.ac.jp
Associate Professor Keiji UCHIYAMAAssociate Professor
Keiji UCHIYAMA
TEL : 088-633-9256
E-mail : ku200@ier.tokushima-u.ac.jp
千田淳司Assistant Professor
Junji CHIDA
TEL : 088-633-7439
E-mail : j-chida@ier.tokushima-u.ac.jp