Neuroscience Seminar Series
Friday, October 12th. 2018, 11:30 am, R229 (2rd Floor), Centre Universitaire des Saints-Pères, 45 rue des Saints-Pères, 75006 Paris
Seung-Jae Lee Professor , Seoul National University College of Medicine
Title: Interplay between protein aggregation and neuroinflammation in Parkinson disease
Synucleinopathies are neurological disorders, characterized by neuronal and glial deposition of a-synuclein aggregates. These disorders include Parkinson’s disease (PD), dementi with Lewy bodies, and multiple systematrophy. Cell-to-cell propagation of these aggregates are thought to be the underlying mechanism of aggregate spreading in patients’ brain and perhaps of clinical progression. Interfering with the aggregate propagation can thus be a potential strategy for halting the disease progression. However, the mechanism by which a-synuclein aggregates spread remains undefined. Here, I present the evidence that a-synuclein aggregates are perpetually transmitted through a continuous cycle involving uptake of external aggregates, co-aggregation with endogenous a-synuclein, and exocytosis of the co-aggregates. Moreover, we found that glucocerebrosidase 1 depletion, which has previously been strongly associated with PD and increased cognitive impairment, promoted propagation of a-synuclein aggregates. Depletion of other genes such as ctsd (cathepsin D) resulted in lysosomal dysfunctions and further confirmed that lysosomal dysfunction is the key modulator of spreading of synucleinopathy. These studies define how a-synuclein aggregates spread among neuronal cells and explain how lysosomal dysfunction increase the risk of developing PD and other synucleinopathies. Another important issue regarding the aggregate propagation is the identification of receptors that mediate the propagation process. Recently, my lab identified toll-like receptor 2 (TLR2), an innate immune receptor, as the receptor for neuron-released a-synuclein oligomers in microglia. I will show evidence that TLR2 plays an important role in cell-to-cell propagation of a-synuclein aggregates, regulating both secretion and uptake of the aggregates. Furthermore, administration of a neutralizing antibody for TLR2 interferes with the intercellular propagation of a-synuclein and thus, alleviates synucleinopathy lesions and neuroinflammation. I propose the anti-TLR2 treatment as a therapeutic strategy for Parkinson’s disease and related synucleinopathies.
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