Abstract
BackgroundThe accumulation of misfolded proteins appears as a fundamental pathogenic process in human neurodegenerative diseases. In the case of synucleinopathies such as Parkinson’s disease (PD) or dementia with Lewy bodies (DLB), the intraneuronal deposition of aggregated alpha-synuclein (αS) is a major characteristic of the disease, but the molecular basis distinguishing the disease-associated protein (αSD) from its normal counterpart remains poorly understood. However, recent research suggests that a prion-like mechanism could be involved in the inter-cellular and inter-molecular propagation of aggregation of the protein within the nervous system.ResultsOur data confirm our previous observations of disease acceleration in a transgenic mouse line (M83) overexpressing a mutated (A53T) form of human αS, following inoculation of either brain extracts from sick M83 mice or fibrillar recombinant αS. A similar phenomenon is observed following a “second passage” in the M83 mouse model, including after stereotactic inoculations into the hippocampus or cerebellum. For further molecular analyses of αSD, we designed an ELISA test that identifies αSD specifically in sick mice and in the brain regions targeted by the pathological process in this mouse model. αSD distribution, mainly in the caudal brain regions and spinal cord, overall appears remarkably uniform, whatever the conditions of experimental challenge. In addition to specific detection of αSD immunoreactivity using an antibody against Ser129 phosphorylated αS, similar results were observed in ELISA with several other antibodies against the C-terminal part of αS, including an antibody against non phosphorylated αS. This also indicated consistent immunoreactivity of the murine αS protein specifically in the affected brain regions of sick mice.ConclusionsPrion-like behaviour in propagation of the disease-associated αS was confirmed with the M83 transgenic mouse model, that could be followed by an ELISA test. The ELISA data question their possible relationship with the conformational differences between the disease-associated αS and its normal counterpart.
Highlights
Pathological accumulation of misfolded alpha-synuclein plays a central role in the pathogenesis of synucleinopathies, human neuro-degenerative diseases including Parkinson’s Diseases (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) [1]
We previously described the acceleration of a synucleinopathy in a transgenic mouse model expressing the A53T mutated human αS protein, when mice were intra-cerebrally inoculated with brain extracts prepared from sick old M83 mice [5]
As αSD has never been detected in M83 mice younger than 4– 6 months [4,5,10,15,17], this likely represents detection of normal human αS overexpressed in M83 mice, which remains limited under these ELISA conditions
Summary
Pathological accumulation of misfolded alpha-synuclein (αS) plays a central role in the pathogenesis of synucleinopathies, human neuro-degenerative diseases including Parkinson’s Diseases (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) [1]. Considerable interest has recently been shown in the hypothesis that αS aggregation could involve a prion-like mechanism for its propagation, involving self-replication and spreading of a misfolded β-sheet enriched pathogenic conformer derived from the normal protein [4,5]. This was triggered by observations of Lewy bodies and neurites in the embryonic mesencephalic neurons grafted in PD patients’brains, when examined over 10 years following the transplant procedure [6,7]. Recent research suggests that a prion-like mechanism could be involved in the inter-cellular and inter-molecular propagation of aggregation of the protein within the nervous system
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