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Endogenous prion protein conversion is required for prion‐induced neuritic alterations and neuronal death
Author(s) -
Cronier Sabrina,
Carimalo Julie,
Schaeffer Brigitte,
Jaumain Emilie,
Béringue Vincent,
Miquel MarieChristine,
Laude Hubert,
Peyrin JeanMichel
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.11-201772
Subject(s) - neurodegeneration , neurotoxicity , scrapie , programmed cell death , microbiology and biotechnology , biology , neuron , endogeny , neurotoxin , chemistry , prion protein , neuroscience , apoptosis , biochemistry , pathology , medicine , disease , organic chemistry , toxicity
Prions cause fatal neurodegenerative conditions and result from the conversion of host‐encoded cellular prion protein (PrP C ) into abnormally folded scrapie PrP (PrP Sc ). Prions can propagate both in neurons and astrocytes, yet neurotoxicity mechanisms remain unclear. Recently, PrP C was proposed to mediate neurotoxic signaling of β‐sheet‐rich PrP and non‐PrP conformers independently of conversion. To investigate the role of astrocytes and neuronal PrP C in prion‐induced neurodegeneration, we set up neuron and astrocyte primary cocultures derived from PrP transgenic mice. In this system, prion‐infected astrocytes delivered ovine PrP Sc to neurons lacking PrP C (prion‐resistant), or expressing a PrP C convertible (sheep) or not (mouse, human). We show that interaction between neuronal PrP C and exogenous PrP Sc was not sufficient to induce neuronal death but that efficient PrP C conversion was required for prion‐associated neurotoxicity. Prion‐infected astrocytes markedly accelerated neurodegeneration in homologous cocultures compared to infected single neuronal cultures, despite no detectable neurotoxin release. Finally, PrP Sc accumulation in neurons led to neuritic damages and cell death, both potentiated by glutamate and reactive oxygen species. Thus, conversion of neuronal PrP C rather than PrP C ‐mediated neurotoxic signaling appears as the main culprit in prion‐induced neurodegeneration. We suggest that active prion replication in neurons sensitizes them to environmental stress regulated by neighboring cells, including astrocytes.— Cronier, S., Carimalo, J., Schaeffer, B., Jaumain, E., Béringue, V., Miquel, M.‐C., Laude, H., Peyrin, J.‐M. Endogenous prion protein conversion is required for prion‐induced neuritic alterations and neuronal death. FASEB J. 26, 3854–3861 (2012). www.fasebj.org