CSF-derived extracellular vesicles from patients with Parkinson's disease induce symptoms and pathology.

ABSTRACT

Parkinson's disease is characterized by the gradual appearance of intraneuronal inclusions that are primarily composed of misfolded α-synuclein protein, leading to cytotoxicity and neural death. Recent in vitro and in vivo studies suggest that misfolded α-synuclein may spread transcellularly in a prion-like manner, inducing pathological aggregates in healthy neurons, and is disseminated via secretion of extracellular vesicles. Accordingly, extracellular vesicles derived from brain lysates and CSF of patients with Parkinson's disease were shown to facilitate α-synuclein aggregation in healthy cells. Prompted by the hypothesis of Braak and colleagues that the olfactory bulb is one of the primary propagation sites for the initiation of Parkinson's disease, we sought to investigate the role of extracellular vesicles in the spread of α-synuclein and progression of Parkinson's disease through the olfactory bulb. Extracellular vesicles derived from the CSF of patients diagnosed with Parkinson's disease or with a non-synucleinopathy neurodegenerative disorder were administered intranasally to healthy mice, once daily over 4 days. Three months later, mice were subjected to motor and non-motor tests. Functional impairments were elucidated by histochemical analysis of midbrain structures relevant to Parkinson's disease pathology, 8 months after EVs treatment. Mice treated with extracellular vesicles from the patients with Parkinson's disease displayed multiple symptoms consistent with prodromal and clinical-phase Parkinson's disease such as hyposmia, motor behaviour impairments and high anxiety levels. Furthermore, their midbrains showed widespread α-synuclein aggregations, dopaminergic neurodegeneration, neuroinflammation and altered autophagy activity. Several unconventional pathologies were also observed, such as α-synuclein aggregations in the red nucleus, growth of premature grey hair and astrogliosis. Collectively, these data indicate that intranasally administered extracellular vesicles derived from the CSF of patients with Parkinson's disease can propagate α-synuclein aggregation in vivo and trigger Parkinson's disease-like symptoms and pathology in healthy mice.