Selective insolubility of alpha-synuclein in human Lewy body diseases is recapitulated in a transgenic mouse model.
alpha-Synuclein (alpha-SYN) is deposited in intraneuronal cytoplasmic inclusions (Lewy bodies, LBs) characteristic for Parkinson's disease (PD) and LB dementias. alpha-SYN forms LB-like fibrils in vitro, in contrast to its homologue beta-SYN. Here we have investigated the solubility of SYNs in human LB diseases and in transgenic mice expressing human wild-type and PD-associated mutant [A30P]alpha-SYN driven by the brain neuron-specific promoter, Thy1. Distinct alpha-SYN species were detected in the detergent-insoluble fractions from brains of patients with PD, dementia with LBs, and neurodegeneration with brain iron accumulation type 1 (formerly known as Hallervorden-Spatz disease). Using the same extraction method, detergent-insolubility of human alpha-SYN was observed in brains of transgenic mice. In contrast, neither endogenous mouse alpha-SYN nor beta-SYN were detected in detergent-insoluble fractions from transgenic mouse brains. The nonamyloidogenic beta-SYN was incapable of forming insoluble fibrils because amino acids 73 to 83 in the central region of alpha-SYN are absent in beta-SYN. In conclusion, the specific accumulation of detergent-insoluble alpha-SYN in transgenic mice recapitulates a pivotal feature of human LB diseases.
Kahle
P J
PJ
Laboratory for Alzheimer's and Parkinson's Disease Research, the Department of Biochemistry, Ludwig Maximilians University, Munich, Germany. pkahle@pbm.med.uni-muenchen.de
Neumann
M
M
Ozmen
L
L
Müller
V
V
Odoy
S
S
Okamoto
N
N
Jacobsen
H
H
Iwatsubo
T
T
Trojanowski
J Q
JQ
Takahashi
H
H
Wakabayashi
K
K
Bogdanovic
N
N
Riederer
P
P
Kretzschmar
H A
HA
Haass
C
C
D000596:Amino Acids / Q000235:genetics; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D003902:Detergents; D004195:Disease Models, Animal; D006801:Humans; D020961:Lewy Body Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D012995:Solubility; D013347:Subcellular Fractions; D013574:Synaptosomes / Q000378:metabolism; D051843:Synucleins; D051844:alpha-Synuclein
D000596:Amino Acids; D003902:Detergents; D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; C497605:Snca protein, mouse; D051843:Synucleins; D051844:alpha-Synuclein