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Regular Article |
-Synuclein in Human Lewy Body Diseases Is Recapitulated in a Transgenic Mouse Model
From the Laboratory for Alzheimer’s and Parkinson’s Disease
Research,*
the Department of Biochemistry and the Department
of Neuropathology,
Ludwig Maximilians
University, Munich, Germany; Pharma Research
Genomics,
F. Hoffmann–La Roche Ltd., Basel,
Switzerland; the Department of Neuropathology and
Neuroscience,
Graduate School of
Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan; the
Department of Pathology and Laboratory Medicine,¶
Center for Neurodegenerative Disease Research, University of
Pennsylvania, School of Medicine, Philadelphia, Pennsylvania; the
Department of Pathology,||
Brain Research Institute,
Niigata University, Niigata, Japan; the Department of
Neuropathology,**
Institute of Brain Science,
Hirosaki University School of Medicine, Hirosaki, Japan; the Department
of Clinical Neuroscience,
Geriatric Section, Huddinge Brain Bank, Huddinge, Sweden; and the
Department of Psychiatry,
Clinical Neurochemistry and The National Parkinson Foundation Center of
Excellence Research Laboratories, Julius Maximilians University,
Würzburg, Germany
-Synuclein (-SYN) is deposited in intraneuronal cytoplasmic
inclusions (Lewy bodies, LBs) characteristic for Parkinson’s
disease (PD) and LB dementias. -SYN forms LB-like fibrils in
vitro, in contrast to its homologue ß-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]-SYN driven by the brain neuron-specific promoter,
Thy1. Distinct -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 -SYN was
observed in brains of transgenic mice. In contrast, neither
endogenous mouse -SYN nor ß-SYN were detected in
detergent-insoluble fractions from transgenic mouse brains. The
nonamyloidogenic ß-SYN was incapable of forming insoluble fibrils
because amino acids 73 to 83 in the central region of -SYN are
absent in ß-SYN. In conclusion, the specific accumulation of
detergent-insoluble -SYN in transgenic mice recapitulates a pivotal
feature of human LB diseases.
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