TY - JOUR
T1 - Overexpression of synphilin-1 promotes clearance of soluble and misfolded alpha-synuclein without restoring the motor phenotype in aged A30P transgenic mice
AU - Casadei, Nicolas
AU - Pö hler, Anne Maria
AU - Tomás-Zapico, Cristina
AU - Torres-Peraza, Jesús
AU - Schwedhelm, Ivo
AU - Witz, Annemarie
AU - Zamolo, Irina
AU - De Heer, Raymond
AU - Spruijt, Berry
AU - Noldus, Lucas P.J.J.
AU - Klucken, Jochen
AU - Lucas, José J.
AU - Kahle, Philipp J.
AU - Krüger, Rejko
AU - Riess, Olaf
AU - Nuber, Silke
N1 - Funding Information:
This work was supported by a European Commission Marie Curie Initial Training Network Grant Agreement: 215618 to O.R.; Federal Ministry of Education and Research (01GN0979), the Albert-Raps Foundation, grants of the University Hospital Erlangen (ELAN No. 08.11.05.1; IZKF No. TP9), Bavaria California Technology Center (BaCaTeC), the Bavarian State Ministry of Sciences, Research, and the Arts, ForNeuroCell, the Spanish Ministry of Science and by Fundación Ramón Areces. S.N. is a fellow of the German Parkinson Society.
PY - 2014/2
Y1 - 2014/2
N2 - Lewy bodies and neurites are the pathological hallmark of Parkinson's disease. These structures arecomposed of fibrillized and ubiquitinated alpha-synuclein suggesting that impairedprotein clearance is an important event in aggregate formation. The A30P mutation is known for its fast oligomerization, but slow fibrillization rate. Despite its toxicity to neurons, mechanisms involved in either clearance or conversion of A30P alpha-synuclein from its soluble state into insoluble fibrils and their effects in vivo are poorly understood. Synphilin-1 is present in Lewy bodies, interacting with alpha-synuclein in vivo and in vitro and promotes its sequestration into aggresomes, which are thought to act as cytoprotective agents facilitating protein degradation.Wetherefore crossed animals overexpressing A30P alpha-synuclein with synphilin-1 transgenic mice to analyze its impact on aggregation, protein clearance and phenotype progression. We observed that co-expression of synphilin-1 mildly delayed the motor phenotype caused by A30P alpha-synuclein. Additionally, the presence of N- and C-terminal truncated alpha-synuclein species and fibrils were strongly reduced in double-transgenic mice when compared with single-transgenic A30P mice. Insolubility of mutant A30P and formation of aggresomes was still detectable inageddouble-transgenic mice, paralleledbyanincreaseof ubiquitinatedproteinsandhigh autophagic activity. Hence, this study supports the notion that co-expression of synphilin-1 promotes formation of autophagicsusceptible aggresomes and consecutively the degradation of human A30P alpha-synuclein. Notably, although synphilin-1 overexpression significantly reduced formation of fibrils and astrogliosis in aged animals, a similar phenotype is present in single- and double-transgenic mice suggesting additional neurotoxic processes in disease progression.
AB - Lewy bodies and neurites are the pathological hallmark of Parkinson's disease. These structures arecomposed of fibrillized and ubiquitinated alpha-synuclein suggesting that impairedprotein clearance is an important event in aggregate formation. The A30P mutation is known for its fast oligomerization, but slow fibrillization rate. Despite its toxicity to neurons, mechanisms involved in either clearance or conversion of A30P alpha-synuclein from its soluble state into insoluble fibrils and their effects in vivo are poorly understood. Synphilin-1 is present in Lewy bodies, interacting with alpha-synuclein in vivo and in vitro and promotes its sequestration into aggresomes, which are thought to act as cytoprotective agents facilitating protein degradation.Wetherefore crossed animals overexpressing A30P alpha-synuclein with synphilin-1 transgenic mice to analyze its impact on aggregation, protein clearance and phenotype progression. We observed that co-expression of synphilin-1 mildly delayed the motor phenotype caused by A30P alpha-synuclein. Additionally, the presence of N- and C-terminal truncated alpha-synuclein species and fibrils were strongly reduced in double-transgenic mice when compared with single-transgenic A30P mice. Insolubility of mutant A30P and formation of aggresomes was still detectable inageddouble-transgenic mice, paralleledbyanincreaseof ubiquitinatedproteinsandhigh autophagic activity. Hence, this study supports the notion that co-expression of synphilin-1 promotes formation of autophagicsusceptible aggresomes and consecutively the degradation of human A30P alpha-synuclein. Notably, although synphilin-1 overexpression significantly reduced formation of fibrils and astrogliosis in aged animals, a similar phenotype is present in single- and double-transgenic mice suggesting additional neurotoxic processes in disease progression.
UR - http://www.scopus.com/inward/record.url?scp=84892468324&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddt467
DO - 10.1093/hmg/ddt467
M3 - Article
C2 - 24064336
AN - SCOPUS:84892468324
SN - 0964-6906
VL - 23
SP - 767
EP - 781
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 3
M1 - ddt467
ER -