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Project Topic
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The gradual accumulation of α-synuclein (α-Syn) and tau aggregates is characteristic of many neurodegenerative diseases, commonly referred to as synucleinopathies and tauopathies, respectively. α-Syn and tau share remarkable common features and the frequent co-occurrence of aggregates of both proteins, e.g. in dementia with Lewy bodies (DLB), blurs the borders between these two disease classes and indicates common denominators. Molecular chaperones assist folding and degradation of unfolded and misfolded proteins and are central for maintaining cellular protein homeostasis. However, during aging, the capacity of chaperones to maintain a healthy proteome becomes less efficient or impaired and misfolded proteins accumulate. Several studies suggest that targeting Hsps can be successful in aggregation diseases like Familial amyloid polyneuropathy (Kelly)1 or cataract (Gestwick)2 and overexpression of Hsp70 (co)chaperones ameliorates α-Syn and tau dependent cell toxicity in various models. Work from the applicants (Kampinga, Melki and Hansen) shows that Hsp70s and other components of the cellular chaperone system counteract oligomerisation and fibril formation of α-Syn, tau and other amyloidogenic proteins, and data from the other applicants (Bukau & Nussbaum-Krammer) indicate a powerful Hsp70-based α-Syn fibril disassembly activity. This reveals the therapeutic potential of the Hsp70 chaperone system, although targeting Hsp70s themselves likely has side effects given their involvement in many different cellular processes. Hsp70 machines however, critically depend on the cooperation with co-chaperones, including members of the large families of DNAJs and nucleotide exchange factors, which provide substrate specificity and control substrate release, and thereby determine the nature and fate of Hsp70 substrates (e.g., refolding vs. degradation). Hsp70 cochaperones therefore are critical constituents of the Hsp70 machinery acting in protein quality control and likely constitute more specific targets for therapy. The overall goal of this project is to discover and investigate the individual edges and shared hubs in the Hsp70/co-chaperone network(s) involved in prevention of aggregation and promotion of disaggregation of α-Syn and tau, as well as combatting cell-to-cell spreading of pathological α-Syn and tau. We will use an integrated approach, combining complementary methodologies and model systems, ranging from in vitro to cell culture to worm, fly and mouse models, to identify chaperone networks targeting α-Syn and tau, characterize their mechanism of action and test their therapeutic potential.
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