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.

Brain-derived exosomes from dementia with Lewy bodies propagate α-synuclein pathology

“…Studies investigating plaque initiation found Aβ plaques in animal brains intracranially injected with AD patient brain homogenates [1, 37]. Neurofibrillary tangles and Lewy Bodies were also seen in rodent brains injected with brains homogenates of tauopathy and synucleinopathy patients, respectively [10, 24]. The seeding of exogenous misfolded proteins initiated the aggregation of endogenous non-diseased protein, a characteristic similar to prion proteins involved in spongiform encephalopathy.…”

Safety and Tolerability of Multiple Ascending Doses of PRX002/RG7935, an Anti–α-Synuclein Monoclonal Antibody, in Patients With Parkinson Disease

“…4,5 Injection of recombinant preformed α-synuclein fibrils into specified brain regions in mice leads to intraneuronal aggregation of α-synuclein and propagation of the pathology, similar to what is observed in PD, indicating that an extracellular form of aggregated α-synuclein may be involved in this pathomechanism. [30][31][32][33][34][35] In preclinical studies, the murine homologue of PRX002 reduced intracellular α-synuclein pathology, protected neurons, and ameliorated cognitive and motor behavior deficits in multiple mouse models of α-synucleinopathy. 9,11,12,15,16 Targeting toxic proteins with monoclonal antibodies is also being evaluated as a potential therapeutic strategy in other neurodegenerative diseases.…”

Oligomeropathies and pathogenesis of Alzheimer and Parkinson's diseases

“…Accordingly, with prion‐like spreading, it was possible to identify different strain conformations and seeding propensity, leading to distinct behavioral and histopathological phenotypes . Peripheral injections, intramuscular, intravenous, or intragastric, also induced cerebral α‐syn neuropathology in transgenic and wild‐type mice . These results indicate that inoculation of fibers, rather than oligomers, induces the propagation of LB/LN‐like inclusions throughout the brain.…”