Transmission of Soluble and Insoluble α-Synuclein to Mice.

Abstract

The neurodegenerative synucleinopathies, which include Parkinson disease, multiple-system atrophy, and Lewy body disease, are characterized by the presence of abundant neuronal inclusions called Lewy bodies and Lewy neurites. These disorders remain incurable, and a greater understanding of the pathologic processes is needed for effective treatment strategies to be developed. Recent data suggest that pathogenic misfolding of the presynaptic protein, α-synuclein (α-syn), and subsequent aggregation and accumulation are fundamental to the disease process. It is hypothesized that the misfolded isoform is able to induce misfolding of normal endogenous α-syn, much like what occurs in the prion diseases. Recent work highlighting the seeding effect of pathogenic α-syn has largely focused on the detergent-insoluble species of the protein. In this study, we performed intracerebral inoculations of the sarkosyl-insoluble or sarkosyl-soluble fractions of human Lewy body disease brain homogenate and show that both fractions induce CNS pathology in mice at 4 months after injection. Disease-associated deposits accumulated both near and distal to the site of the injection, suggesting a cell-to-cell spread via recruitment of α-syn. These results provide further insight into the prion-like mechanisms of α-syn and suggest that disease-associated α-syn is not homogeneous within a single patient but might exist in both soluble and insoluble isoforms.

• Authors: Daryl Rhys Jones, Marion Delenclos, AnnMarie T Baine, Michael DeTure, Melissa E Murray, Dennis W Dickson, Pamela J McLean
• Journal: Journal of neuropathology and experimental neurology (J Neuropathol Exp Neurol) Vol. 74 Issue 12 Pg. 1158-69 (Dec 2015) ISSN: 1554-6578 [Electronic] England
• PMID: 26574670 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Aif1 protein, mouse
• Calcium-Binding Proteins
• Detergents
• Glial Fibrillary Acidic Protein
• Microfilament Proteins
• Platelet-Derived Growth Factor
• alpha-Synuclein
• sarkosyl
• Sarcosine

Topics

• Adaptation, Ocular (genetics)
• Age Factors
• Aged
• Animals
• Brain (drug effects, metabolism, pathology, ultrastructure)
• Calcium-Binding Proteins (metabolism)
• Detergents (pharmacology)
• Disease Models, Animal
• Exploratory Behavior (physiology)
• Female
• Glial Fibrillary Acidic Protein (metabolism)
• Humans
• Lewy Body Disease (chemically induced, pathology, physiopathology, therapy)
• Male
• Maze Learning (physiology)
• Mice
• Mice, Transgenic
• Microfilament Proteins (metabolism)
• Microscopy, Electron
• Muscle Strength (genetics)
• Platelet-Derived Growth Factor (genetics, metabolism)
• Sarcosine (analogs & derivatives, pharmacology)
• alpha-Synuclein (administration & dosage, drug effects, genetics, metabolism)