Targeting the inflammasome in Parkinson's disease.

Parkinson's disease (PD) is one of the most common neurodegenerative diseases in which neuroinflammation plays pivotal roles. An important mechanism of neuroinflammation is the NLRP3 inflammasome activation that has been implicated in PD pathogenesis. In this perspective, we will discuss the relationship of some key PD-associated proteins including α-synuclein and Parkin and their contribution to inflammasome activation. We will also review promising inhibitors of NLRP3 inflammasome pathway that have potential as novel PD therapeutics. Finally, we will provide a summary of current and potential in vitro and in vivo models that are available for therapeutic discovery and development.

Parkinson's Disease-Specific Autoantibodies against the Neuroprotective Co-Chaperone STIP1.

Parkinson's disease (PD) is a debilitating movement disorder characterised by the loss of dopaminergic neurons in the substantia nigra. As neuroprotective agents mitigating the rate of neurodegeneration are unavailable, the current therapies largely focus only on symptomatic relief. Here, we identified stress-inducible phosphoprotein 1 (STIP1) as a putative neuroprotective factor targeted by PD-specific autoantibodies. STIP1 is a co-chaperone with reported neuroprotective capacities in mouse Alzheimer's disease and stroke models. With human dopaminergic neurons derived from induced pluripotent stem cells, STIP1 was found to alleviate staurosporine-induced neurotoxicity. A case-control study involving 50 PD patients (average age = 62.94 ± 8.48, Hoehn and Yahr >2 = 55%) and 50 age-matched healthy controls (HCs) (average age = 63.1 ± 8) further revealed high levels of STIP1 autoantibodies in 20% of PD patients compared to 10% of HCs. Using an overlapping peptide library covering the STIP1 protein, we identified four PD-specific B cell epitopes that were not recognised in HCs. All of these epitopes were located within regions crucial for STIP1's chaperone function or prion protein association. Our clinical and neuro-immunological studies highlight the potential of the STIP1 co-chaperone as an endogenous neuroprotective agent in PD and suggest the possible involvement of autoimmune mechanisms via the production of autoantibodies in a subset of individuals.

Role of MicroRNAs in Parkinson's Disease.

Parkinson's disease (PD) is a disabling neurodegenerative disease that manifests with resting tremor, bradykinesia, rigidity and postural instability. Since the discovery of microRNAs (miRNAs) in 1993, miRNAs have been shown to be important biological molecules involved in diverse processes to maintain normal cellular functions. Over the past decade, many studies have reported dysregulation of miRNA expressions in PD. Here, we identified 15 miRNAs from 34 reported screening studies that demonstrated dysregulation in the brain and/or neuronal models, cerebrospinal fluid (CSF) and blood. Specific miRNAs-of-interest that have been implicated in PD pathogenesis include miR-30, miR-29, let-7, miR-485 and miR-26. However, there are several challenges and limitations in drawing definitive conclusions due to the small sample size in clinical studies, varied laboratory techniques and methodologies and their incomplete penetrance of the blood-brain barrier. Developing an optimal delivery system and unravelling druggable targets of miRNAs in both experimental and human models and clinical validation of the results may pave way for novel therapeutics in PD.

Response of Neutrophils to Extracellular Haemoglobin and LTA in Human Blood System.

BACKGROUND: Haemolytic infection lyses red blood cells, releasing haemoglobin (Hb) into the plasma. Although recent studies showed that immune cells recognize redox-active cytotoxic extracellular Hb (metHb) bound to pathogen-associated molecular patterns (PAMPs), currently available information is limited to experiments performed in defined conditions using single cell lines. Therefore, a systemic approach targeting primary whole blood cells is required to better understand the cellular immune defence against metHb and PAMPs, when under a haemolytic infection. METHODS: We investigated how human white blood cells, including neutrophils, respond to metHb and lipoteichoic acid (LTA) by measuring reactive oxygen species (ROS), signalling mediators (ERK and p38), NF-κB, cytokines, elastase secretion and cell activation markers. FINDINGS: metHb activates NF-κB in TLR2-expressing HEK293 cells but not in normal or TLR9-expressing HEK293 cells. Treatment of isolated neutrophils with metHb increased production of ROS and expressions of IL-8, TNFα, and CD11b, which were further enhanced by metHb + LTA complex. While LTA stimulated the survival of neutrophils, it caused apoptotic cell death when complexed with metHb. The activation of neutrophils by metHb + LTA was subdued by the presence of other types of white blood cells. INTERPRETATION: metHb and metHb + LTA complex are ligands of TLR2, inducing an unconventional TLR signalling pathway. Neutrophils are a highly sensitive cell type to metHb + LTA complex. During a haemolytic infection, white blood cells in the vicinity crosstalk to modulate neutrophil TLR-signalling induced by metHb and LTA.