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 is 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 post-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 homogenous within a single patient but might exist in both soluble and insoluble isoforms.

Oligomeropathies and pathogenesis of Alzheimer and Parkinson's diseases

“…110 Peripheral injections, intramuscular, intravenous, or intragastric, also induced cerebral a-syn neuropathology in transgenic and wild-type mice. [110][111][112][113] These results indicate that inoculation of fibers, rather than oligomers, induces the propagation of LB/LN-like inclusions throughout the brain. The persistence of inoculated fibers into the brains might justify their efficacy in inducing the spread of pathology.…”

LRRK2 Kinase Inhibition Rescues Deficits in Lysosome Function Due to Heterozygous GBA1 Expression in Human iPSC-Derived Neurons

“…Multiple lines of evidence support the cell-to-cell transfer of insoluble αSyn (Braak et al, 2003;Danzer et al, 2012;Luk et al, 2012;Volpicelli-Daley et al, 2014;Jones et al, 2015). Additionally, GCase-null mice were found to exhibit an accumulation of endogenous αSyn and the formation of its insoluble oligomers (Mazzulli et al, 2011;Sardi et al, 2011).…”

Autonomic ganglionic injection of α-synuclein fibrils as a model of pure autonomic failure α-synucleinopathy

“…The paraffin-embedded tissues were cut into 4 μm thick sections with a Rotary Microtome (Leica RM2235, Leica, Nussloch, Germany). Then, sections were mounted on glass slides, dehydrated and deparaffinized 46,47 . Nonspecific sites of antigens were blocked with normal sera of the host animal species of the secondary antibodies.…”