Abnormal synaptic protein expression and cell death in murine scrapie

TY - JOUR

T1 - Abnormal synaptic protein expression and cell death in murine scrapie

AU - Sisó, S

AU - Puig, B

AU - Varea, R

AU - Vidal, E

AU - Acín, C

AU - Prinz, M

AU - Montrasio, F

AU - Badiola, J

AU - Aguzzi, A

AU - Pumarola, M

AU - Ferrer, I

AU - Puig Martorell, Berta

PY - 2002/6/1

Y1 - 2002/6/1

N2 - Reduced expression of synaptophysin p38, synaptic-associated protein of molecular weight 25,000 (SNAP-25), syntaxin-1, synapsin-1, and alpha- and beta-synuclein, matching the distribution of spongiform degeneration, was found in the neurological phase of scrapie-infected mice. In addition, synaptophysin and SNAP-25 were accumulated in isolated neurons, mainly in the thalamus, midbrain and pons, and granular deposits of alpha- and beta-synuclein were present in the neuropil of the same areas. No modifications in the steady state levels of Bcl-2, Bax, Fas and Fas ligand were observed following infection. Yet antibodies against the c-Jun N-terminal peptide, which cross-react with products emerging after caspase-mediate proteolysis, recognize coarse granular deposits in the cytoplasm of reactive microglia. In situ end-labeling of nuclear DNA fragmentation showed positive nuclei with extreme chromatin condensation in the thalamus, pons, hippocampus and, in particular, the granular layer of the cerebellum. More importantly, expression of cleaved caspase-3, a major executioner of apoptosis, was seen in a few cells in the same regions, thus indicating that cell death by apoptosis in scrapie-infected mice is associated with caspase-3 activation. The present findings support the concept that synaptic pathology is a major substrate of neurological impairment and that caspase-3 activation may play a pivotal role in apoptosis in experimental scrapie. However, there is no correlation between decreased synaptic protein expression and caspase-3-associated apoptosis, which suggests that in addition to abnormal prion protein deposition, there may be other factors that distinctively influence synaptic vulnerability and cell death in murine scrapie.

AB - Reduced expression of synaptophysin p38, synaptic-associated protein of molecular weight 25,000 (SNAP-25), syntaxin-1, synapsin-1, and alpha- and beta-synuclein, matching the distribution of spongiform degeneration, was found in the neurological phase of scrapie-infected mice. In addition, synaptophysin and SNAP-25 were accumulated in isolated neurons, mainly in the thalamus, midbrain and pons, and granular deposits of alpha- and beta-synuclein were present in the neuropil of the same areas. No modifications in the steady state levels of Bcl-2, Bax, Fas and Fas ligand were observed following infection. Yet antibodies against the c-Jun N-terminal peptide, which cross-react with products emerging after caspase-mediate proteolysis, recognize coarse granular deposits in the cytoplasm of reactive microglia. In situ end-labeling of nuclear DNA fragmentation showed positive nuclei with extreme chromatin condensation in the thalamus, pons, hippocampus and, in particular, the granular layer of the cerebellum. More importantly, expression of cleaved caspase-3, a major executioner of apoptosis, was seen in a few cells in the same regions, thus indicating that cell death by apoptosis in scrapie-infected mice is associated with caspase-3 activation. The present findings support the concept that synaptic pathology is a major substrate of neurological impairment and that caspase-3 activation may play a pivotal role in apoptosis in experimental scrapie. However, there is no correlation between decreased synaptic protein expression and caspase-3-associated apoptosis, which suggests that in addition to abnormal prion protein deposition, there may be other factors that distinctively influence synaptic vulnerability and cell death in murine scrapie.

KW - Animals

KW - Antigens, Surface

KW - Brain

KW - Caspase 3

KW - Caspases

KW - Cell Death

KW - Crystallins

KW - Down-Regulation

KW - Female

KW - Immunohistochemistry

KW - Male

KW - Membrane Proteins

KW - Mice

KW - Mice, Inbred C57BL

KW - Mitogen-Activated Protein Kinases

KW - Nerve Degeneration

KW - Nerve Tissue Proteins

KW - Neuroglia

KW - Neurons

KW - PrPC Proteins

KW - Scrapie

KW - Synapses

KW - Synapsins

KW - Synaptophysin

KW - Synaptosomal-Associated Protein 25

KW - Syntaxin 1

KW - Synucleins

KW - beta-Synuclein

KW - p38 Mitogen-Activated Protein Kinases

U2 - 10.1007/s00401-001-0512-6

DO - 10.1007/s00401-001-0512-6

M3 - SCORING: Journal article

C2 - 12012094

VL - 103

SP - 615

EP - 626

JO - ACTA NEUROPATHOL

JF - ACTA NEUROPATHOL

SN - 0001-6322

IS - 6

ER -