No abstract

Protease-activated receptors (PARs) are a novel family of G-protein coupled receptors (GPCRs) whose activation requires the cleavage of the N-terminus by a serine protease. However, recent evidence reveals that alternative routes of activation also occur, that PARs signal via multiple pathways and that pathway activation is activator- dependent. Given our increased understanding of PAR function both under physiological and pathophysiological conditions, one aspect that has remained constant is the link between PAR2 and inflammation. PAR2 is expressed in immune cells of both the innate and adaptive immune system and has been shown to play a role in several peripheral inflammatory conditions. PAR2 is similarly expressed on astrocytes and microglia within the CNS and its activation is either protective or detrimental to CNS function depending on the conditions or disease state investigated. With a clear similarity between the function of PAR2 on both immune cells and CNS glial cells, here we have reviewed their roles in both these systems. We suggest that the recent development of novel PAR2 modulators, including those that show biased signalling, will further increase our understanding of PAR2 function and the development of potential therapeutics for CNS disorders in which inflammation is proposed to play a role.

Several phenotypic differences observed in Parkinson’s disease (PD) patients have been linked to age at onset (AAO). We endeavoured to find out whether these differences are due to the ageing process itself by using a combined dataset of idiopathic PD (n = 430) and healthy controls (HC; n = 556) excluding carriers of known PD-linked genetic mutations in both groups. We found several significant effects of AAO on motor and non-motor symptoms in PD, but when comparing the effects of age on these symptoms with HC (using age at assessment, AAA), only positive associations of AAA with burden of motor symptoms and cognitive impairment were significantly different between PD vs HC. Furthermore, we explored a potential effect of polygenic risk score (PRS) on clinical phenotype and identified a significant inverse correlation of AAO and PRS in PD. No significant association between PRS and severity of clinical symptoms was found. We conclude that the observed non-motor phenotypic differences in PD based on AAO are largely driven by the ageing process itself and not by a specific profile of neurodegeneration linked to AAO in the idiopathic PD patients.

The accumulation of proteinaceous deposits comprised largely of the α-synuclein protein is one of the main hallmarks of Parkinson's disease (PD) and related synucleinopathies. Their progressive development coincides with site-specific phosphorylation, oxidative stress and eventually, compromised neuronal function. However, modeling protein aggregate formation in animal or in vitro models has proven notably difficult. Here, we took advantage of a preclinical organotypic brain slice culture model to study α-synuclein aggregate formation ex vivo. We monitored the progressive and gradual changes induced by α-synuclein such as cellular toxicity, autophagy activation, mitochondrial dysfunction, cellular death as well as α-synuclein modification including site-specific phosphorylation. Our results demonstrate that organotypic brain slice cultures can be cultured for long periods of time and when cultured in the presence of aggregated α-synuclein, the molecular features of PD are recapitulated. Taken together, this ex vivo model allows for detailed modeling of the molecular features of PD, thus enabling studies on the cumulative effects of α-synuclein in a complex environment. This provides a platform to screen potential disease-modifying therapeutic candidates aimed at impeding α-synuclein aggregation and/or cellular transmission. Moreover, this model provides a robust replacement for in vivo studies that do not include behavioral experiments, thus providing a way to reduce the number of animals used in an accelerated timescale.

No abstract