ABSTRACT
Prion diseases are caused by disease -causing isoform of the prion protein (PrP(Sc)) accumulation in the central nervous system. Accumulation of PrP(Sc) induces synaptic dysfunctions, dendritic atrophy, neuronal vacuolation and reactive gliosis. Clinical symptoms are observed after neuronal cell loss. Recently we have reported that Notch-1, which plays important roles in neuronal development is activated in animal and cell models of prion diseases. It is well known that the activation of the Notch signaling pathway induces gliogenesis and suppresses neurogenesis. I will review the previous reports about neurodegeneraion of prion diseases and discuss the possible involvement of Notch-1 in the dendritic atrophy.
Subject(s)
Nerve Degeneration/genetics , Prion Diseases/pathology , Receptor, Notch1/physiology , Animals , Atrophy/genetics , Dendrites/pathology , Disease Models, Animal , Humans , Mice , Receptor, Notch1/metabolism , Signal TransductionABSTRACT
In addition to neuronal vacuolation and astrocytic hypertrophy, dendritic atrophy is a prominent feature of prion disease. Because increased Notch-1 expression and cleavage releasing its intracellular domain (NICD) inhibit both dendrite growth and maturation, we measured their levels in brains from mice inoculated with Rocky Mountain Laboratory (RML) prions. The level of NICD was elevated in the neocortex, whereas the level of beta-catenin, which stimulates dendritic growth, was unchanged. During the incubation period, levels of the disease-causing prion protein isoform, PrPSc, and NICD increased concomitantly in the neocortex. Additionally, increased levels of Notch-1 mRNA and translocation of NICD to the nucleus correlated well with regressive dendritic changes. In scrapie-infected neuroblastoma (ScN2a) cells, the level of NICD was elevated compared with uninfected control (N2a) cells. Long neurofilament protein-containing processes extended from the surface of N2a cells, whereas ScN2a cells had substantially shorter processes. Transfection of ScN2a cells with a Notch-1 small interfering RNA decreased Notch-1 mRNA levels, diminished NICD concentrations, and rescued the long process phenotype. These results suggest that PrPSc in neurons and in ScN2a cells activates Notch-1 cleavage, resulting in atrophy of dendrites in the CNS and shrinkage of processes on the surface of cultured cells. Whether diminishing Notch-1 activation in vivo can prevent or even reverse neurodegeneration in prion disease remains to be established.
Subject(s)
Atrophy , Dendrites/pathology , Prion Diseases/pathology , Receptors, Cell Surface/metabolism , Transcription Factors/metabolism , Active Transport, Cell Nucleus , Animals , Cell Line, Tumor , Disease Models, Animal , Female , Mice , Mice, Inbred Strains , Neocortex/chemistry , Neocortex/metabolism , Neurons/drug effects , Neurons/ultrastructure , PrPSc Proteins/analysis , RNA, Messenger/analysis , RNA, Messenger/drug effects , RNA, Small Interfering/pharmacology , Receptor, Notch1 , Receptors, Cell Surface/genetics , Receptors, Cell Surface/physiology , Transcription Factors/genetics , Transcription Factors/physiologyABSTRACT
Trimethyltin (TMT) is an organic metal known to induce neuronal degeneration in the hippocampus, and abnormal behavior characterized by seizures, increased aggression and memory deficits. We administered TMT to rats and studied the changes of neuropeptide Y (NPY) and somatostatin (SOM) in the hippocampus. Phenobarbital (PB) was administered as an anticonvulsant to assess the effect of seizures on neuropeptide expressions in both dorsal and ventral hippocampus. Histochemically, NPY-immunoreactivity increased 4 days after TMT treatment in the hilus of the hippocampus, then progressively decreased and dropped to a level below control 16 days after TMT treatment. Detection of NPY mRNA by in situ hybridization preceded the detection of NPY by immunohistochemistry. NPY mRNA signals increased in the hilus 2 days after TMT treatment. SOM-immunoreactivity also increased in the hilus of the hippocampus 2 days after TMT treatment, then decreased rapidly to a normal level. Similar changes in SOM mRNA were demonstrated by in situ hybridization. PB treatment significantly inhibited changes of NPY in terms of both immunoreactivity and mRNA expression; however, the same treatment failed to affect changes in SOM expression. This suggests that NPY and SOM act by different mechanisms in TMT-induced neurodegeneration.
Subject(s)
Hippocampus/pathology , Neuropeptide Y/physiology , Seizures/chemically induced , Seizures/physiopathology , Somatostatin/physiology , Trimethyltin Compounds/toxicity , Animals , Anticonvulsants/pharmacology , Benzoxazines , Cell Count , Coloring Agents , Hippocampus/drug effects , Hippocampus/metabolism , Immunohistochemistry , In Situ Hybridization , Male , Neuropeptide Y/biosynthesis , Oxazines , Phenobarbital/pharmacology , RNA, Messenger/biosynthesis , Rats , Rats, Sprague-Dawley , Somatostatin/biosynthesisABSTRACT
The authors report a female patient with sporadic double cortex syndrome who manifested recurrent interictal schizophrenia-like psychoses. She had no mutations in the doublecortin gene but a pericentric inversion of chromosome 9. Neurodevelopmental disturbances and seizures may be associated with her mental dysfunction.
