Diverse cell death pathways result from a single missense mutation in weaver mouse

Antonio Migheli, Roberto Piva, Jianjun Wei, Angelo Attanasio, Stefania Casolino, Marion E. Hodes, Stephen Dlouhy, Shirley A. Bayer, Bernardino Ghetti

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Abstract

Neuronal death affects selectively granule cell precursors of the cerebellum and the dopaminergic neurons of midbrain in the weaver mutant mouse. The weaver phenotype is associated with a missense mutation in the gene coding for the GIRK2 potassium channel, which results in chronic depolarization. Using DNA gel electrophoresis, electron microscopy (EM), the in situ end-labelling (ISEL) technique at the light and EM level, and immunohistochemistry for apoptosis-related proteins c-Jun and proliferating cell nuclear antigen (PCNA), we have investigated the mechanisms of cell death in cerebellum and substantia nigra. Between postnatal day P1 and P21, in the external germinal layer of the cerebellum, most degenerating granule cell precursors were found to aggregate to form clusters. Degenerating cells exhibited strong nuclear staining for ISEL, c-Jun, and PCNA and had a typical apoptotic morphology by EM. Increased c-Jun and ISEL staining were also occasionally seen in Purkinje cells. Between P14 and P21, when dopaminergic neurons start to degenerate, staining for ISEL, c-Jun, and PCNA in weaver substantia nigra was the same as in controls. By EM, however, we found only in weaver mice numerous dopaminergic cells that showed extensive vacuolar and autophagic changes of cytoplasm, preservation of membrane and organelle integrity, and absence of chromatin condensation or DNA fragmentation by EM- ISEL. The combination of vacuolar and autophagic changes identifies a novel type of non-necrotic, nonapoptotic cell death. After biochemical analysis of DNA, a clear-cut laddering, suggestive of oligonucleosomal fragmentation, was present in samples from weaver cerebellum. Cell death diversity appears to be influenced by specific features of target cells. These findings may be relevant for understanding the mechanisms of cell death in neurodegenerative diseases.

Original languageEnglish
Pages (from-to)1629-1638
Number of pages10
JournalAmerican Journal of Pathology
Volume151
Issue number6
StatePublished - Dec 1997

Fingerprint

Neurologic Mutant Mice
Missense Mutation
Electron Microscopy
Cell Death
Cerebellum
Proliferating Cell Nuclear Antigen
Dopaminergic Neurons
Substantia Nigra
Staining and Labeling
G Protein-Coupled Inwardly-Rectifying Potassium Channels
Proto-Oncogene Proteins c-jun
Purkinje Cells
DNA
DNA Fragmentation
Mesencephalon
Neurodegenerative Diseases
Organelles
Chromatin
Electrophoresis
Cytoplasm

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Migheli, A., Piva, R., Wei, J., Attanasio, A., Casolino, S., Hodes, M. E., ... Ghetti, B. (1997). Diverse cell death pathways result from a single missense mutation in weaver mouse. American Journal of Pathology, 151(6), 1629-1638.

Diverse cell death pathways result from a single missense mutation in weaver mouse. / Migheli, Antonio; Piva, Roberto; Wei, Jianjun; Attanasio, Angelo; Casolino, Stefania; Hodes, Marion E.; Dlouhy, Stephen; Bayer, Shirley A.; Ghetti, Bernardino.

In: American Journal of Pathology, Vol. 151, No. 6, 12.1997, p. 1629-1638.

Research output: Contribution to journalArticle

Migheli, A, Piva, R, Wei, J, Attanasio, A, Casolino, S, Hodes, ME, Dlouhy, S, Bayer, SA & Ghetti, B 1997, 'Diverse cell death pathways result from a single missense mutation in weaver mouse', American Journal of Pathology, vol. 151, no. 6, pp. 1629-1638.
Migheli A, Piva R, Wei J, Attanasio A, Casolino S, Hodes ME et al. Diverse cell death pathways result from a single missense mutation in weaver mouse. American Journal of Pathology. 1997 Dec;151(6):1629-1638.
Migheli, Antonio ; Piva, Roberto ; Wei, Jianjun ; Attanasio, Angelo ; Casolino, Stefania ; Hodes, Marion E. ; Dlouhy, Stephen ; Bayer, Shirley A. ; Ghetti, Bernardino. / Diverse cell death pathways result from a single missense mutation in weaver mouse. In: American Journal of Pathology. 1997 ; Vol. 151, No. 6. pp. 1629-1638.
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