Dysfunction of two lysosome degradation pathways of α-synuclein in Parkinson's disease: potential therapeutic targets?

Parkinson＇s disease （PD） is pathologically characterized by the presence of α-synuclein （α-syn）-positive intra-cytoplasmic inclusions named Lewy bodies in the dopaminergic neurons of the substantia nigra. A series of morbid consequences are caused by pathologically high amounts or mutant forms of α-syn, such as defects of membrane trafficking and lipid metabolism. In this review, we consider evidence that both point mutation and overexpression of α-syn result in aberrant degradation in neurons and microglia, and this is associated with the autophagy-lysosome pathway and endosome-lysosome system, leading directly to pathological intracellular aggregation, abnormal externalization and re-internalization cycling （and, in turn, internalization and re-externalization）, and exocytosis. Based on these pathological changes, an increasing number of researchers have focused on these new therapeutic targets, aiming at alleviating the pathological accumulation of α-syn and re-establishing normal degradation.

Association of Source of Memory Complaints and Increased Risk of Cognitive Impairment and Cognitive Decline： A Community-Based Study

Background： Memory complaint is common in the elderly. Recently, it was shown that self-report memory complaint was predictive of cognitive decline. This study aimed to investigate the predictive value of the source of memory complaints on the risk of cognitive impairment and cognitive decline in a community-based cohort. Methods： Data on memory complaints and cognitive function were collected among 1840 Chinese participants （aged ≥55 years old） in an urban community at baseline interview and 5-year follow-up. Incident cognitive impairment was identified based on education-adjusted Mini-Mental State Examination score. Logistic regression model was used to estimate the association between the source of memory complaints and risk of cognitive impairment conversion and cognitive decline, after adjusting for covariates. Results： A total of 1840 participants were included into this study including 1713 normal participants and 127 cognitive impairment participants in 2009. Among 1713 normal participants in 2009, 130 participants were converted to cognitive impairment alter 5 years of follow-up. In 2014, 606 participants were identified as cognitive decline. Both self- and informant-reported memory complaints were associated with an increased risk of cognitive impairment （odds ratio [OR] - 1.60, 95% confidence interval [CI]： 1.04 2.48） and cognitive decline （OR = 1.30, 95% CI： 1.01-1.68）. Furthermore, this association was more significant in males （OR = 2.10, 95% CI： 1.04-4.24 for cognitive impairment and OR - 1.87, 95% CI：1.20-2.99 for cognitive decline） and in higher education level （OR - 1.79, 95% CI： 1.02-3.15 for cognitive impairment and OR = 1.40, 95% CI：1.02-1.91 for cognitive decline）. Conclusions： Both self- and informant-reported memory complaints were associated with an increased risk of cognitive impairment conversion and cognitive decline, especially in persons with male gender and high educational background.