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PARKINSON’S DISEASE PATIENTS CSF-DERIVED EXTRACELLULAR VESICLES SPREAD PATHOLOGY THROUGH INTRANASAL ROUTES
Abstract
Aims
Parkinson’s disease (PD) 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 studies suggest that misfolded α-synuclein may spread transcellularly, inducing pathological aggregates in healthy neurons, and is disseminated via secretion of extracellular vesicles (EVs). Prompted by the hypothesis of Braak et al. that the olfactory bulb is one of the primary propagation sites for the initiation of PD, we sought to investigate the role of EVs in the spread of α-synuclein and progression of PD through the olfactory bulb.
Methods
EVs derived from the cerebrospinal fluid of patients diagnosed with PD or with a nonsynucleinopathy neurodegenerative disorder were administered intranasally to healthy mice. Three months later, mice were subjected to behavior tests and histochemical analysis of midbrain structures.
Results
Mice subjected to the intranasal administration of CSF-derived EVs from PD patients exhibited multiple features consistent with the disease such as motor behavior impairments, α-synuclein aggregations in the substantia nigra and dopaminergic neurodegeneration. In addition, we observed several understudied symptoms such as robust α-synuclein aggregations in the red nucleus, canities, impaired autophagy and astrogliosis of unconventional GFAP isoforms.
Conclusions
Collectively, these data indicate that intranasally administered EVs derived from the CSF of patients with PD can propagate α-synuclein aggregation in vivo and trigger PD-like symptoms and pathology in healthy mice. Deciphering the disrupted pathways leading to definitive parkinsonian symptoms alongside the unconventional pathologies can lead to further resolution of the molecular pathology of PD.