TY - JOUR
T1 - Lethal recessive myelin toxicity of prion protein lacking its central domain
AU - Baumann, Frank
AU - Tolnay, Markus
AU - Brabeck, Christine
AU - Pahnke, Jens
AU - Kloz, Ulrich
AU - Niemann, Hartmut H.
AU - Heikenwalder, Mathias
AU - Rülicke, Thomas
AU - Bürkle, Alexander
AU - Aguzzi, Adriano
PY - 2007/1/24
Y1 - 2007/1/24
N2 - PrPC-deficient mice expressing prion protein variants with large amino-proximal deletions (termed PrPΔF) suffer from neurodegeneration, which is rescued by full-length PrPC. We now report that expression of PrPΔCD, a PrP variant lacking 40 central residues (94-134), induces a rapidly progressive, lethal phenotype with extensive central and peripheral myelin degeneration. This phenotype was rescued dose-dependently by coexpression of full-length PrPC or PrP C lacking all octarepeats. Expression of a PrPC variant lacking eight residues (114-121) was innocuous in the presence or absence of full-length PrPC, yet enhanced the toxicity of PrP ΔCD and diminished that of PrPΔF. Therefore, deletion of the entire central domain generates a strong recessive-negative mutant of PrPC, whereas removal of residues 114-121 creates a partial agonist with context-dependent action. These findings suggest that myelin integrity is maintained by a constitutively active neurotrophic protein complex involving PrPC, whose effector domain encompasses residues 94-134.
AB - PrPC-deficient mice expressing prion protein variants with large amino-proximal deletions (termed PrPΔF) suffer from neurodegeneration, which is rescued by full-length PrPC. We now report that expression of PrPΔCD, a PrP variant lacking 40 central residues (94-134), induces a rapidly progressive, lethal phenotype with extensive central and peripheral myelin degeneration. This phenotype was rescued dose-dependently by coexpression of full-length PrPC or PrP C lacking all octarepeats. Expression of a PrPC variant lacking eight residues (114-121) was innocuous in the presence or absence of full-length PrPC, yet enhanced the toxicity of PrP ΔCD and diminished that of PrPΔF. Therefore, deletion of the entire central domain generates a strong recessive-negative mutant of PrPC, whereas removal of residues 114-121 creates a partial agonist with context-dependent action. These findings suggest that myelin integrity is maintained by a constitutively active neurotrophic protein complex involving PrPC, whose effector domain encompasses residues 94-134.
UR - http://www.scopus.com/inward/record.url?scp=33846498655&partnerID=8YFLogxK
U2 - 10.1038/sj.emboj.7601510
DO - 10.1038/sj.emboj.7601510
M3 - Journal articles
C2 - 17245436
AN - SCOPUS:33846498655
VL - 26
SP - 538
EP - 547
JO - EMBO Journal
JF - EMBO Journal
SN - 0261-4189
IS - 2
ER -