The HMGB1-S100B-RAGE Axis as a Novel Target for Parkinson’s Disease

Supervisors: Dr Peter Teismann, Prof Gernot Riedel and Prof John Forrester

Parkinson's disease (PD) is a neurodegenerative disorder of uncertain pathogenesis characterised by the loss of nigrostriatal dopaminergic neurons, which can be modelled by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).
Recently we have shown that ablation of the receptor-for-advanced-glycation-endproducts (RAGE) leads to neuroprotection. MPTP increased endogenous expression of two inflammatory 'danger' signals: high-mobility group box 1 (HMGB1) and S100B, both ligands for RAGE. Our studies shows that:

(a) S100B toxicity is mediated via RAGE and TNF-α;
(b) ablation of S100B leads to neuroprotection; c) S100B may be a biomarker for PD.

In addition, HMGB1 is released from necrotic and inflammatory cells during inflammation. Administration of a neutralizing antibody against HMGB1 provides neuroprotection, expression of HMGB1 is significantly increased in Parkinson patients, suggesting it could be a biomarker.

Our results suggest that S100B and/or HMGB1 are suitable targets for a neuroprotective treatment in PD. Using a pharmacological approach we will assess inhibitors of S100B (pentamidine) and/or HMGB1 (glycyrrhizin) for their neuroprotection and explore the signalling pathways involved to evaluate the potential for alternative more selective drug targets. Importantly, these experiments will define the role of the HMGB1-S100B-RAGE pathway in PD pathogenesis, and if S100B and/or HMGB1 are suitable targets for treatment of PD patients.