Abstract
Despite converging epidemiological evidence for the inverse relationship of regular caffeine consumption and risk of developing Parkinson's disease (PD) with animal studies demonstrating protective effect of caffeine in various neurotoxin models of PD, whether caffeine can protect against mutant α-synuclein (α-Syn) A53T-induced neurotoxicity in intact animals has not been examined. Here, we determined the effect of chronic caffeine treatment using the α-Syn fibril model of PD by intra-striatal injection of preformed A53T α-Syn fibrils. We demonstrated that chronic caffeine treatment blunted a cascade of pathological events leading to α-synucleinopathy, including pSer129α-Syn-rich aggregates, apoptotic neuronal cell death, microglia, and astroglia reactivation. Importantly, chronic caffeine treatment did not affect autophagy processes in the normal striatum, but selectively reversed α-Syn-induced defects in macroautophagy (by enhancing microtubule-associated protein 1 light chain 3, and reducing the receptor protein sequestosome 1, SQSTM1/p62) and chaperone-mediated autophagy (CMA, by enhancing LAMP2A). These findings support that caffeine—a strongly protective environment factor as suggested by epidemiological evidence—may represent a novel pharmacological therapy for PD by targeting autophagy pathway.
Highlights
Parkinson’s disease (PD) is pathologically characterized by selective degeneration of dopaminergic neurons in the midbrain and the presence of intracellular amyloidogenicα-synuclein (α-Syn) inclusions, known as Lewy bodies and Lewy neurites, which progress from the medulla to midbrain and throughout cortical areas
This PD model has been recently shown to recapitulates many features of PD, including neuron loss and robust formation of α-Syn inclusions, which resemble biochemical and morphological features of Lewy bodies and Lewy neurites found in the PD brain (Volpicelli-Daley et al, 2011; Luk et al, 2012a), and the abnormal seeking and spreading of α-Syn inclusions throughout the brain. This is in contrast with α-Syn soluble oligomeric species that are thought to be the most neurotoxic species, but they apparently do not cause inclusion formation (Volpicelli-Daley et al, 2011, 2014). Using this PD model coupled with the chronic caffeine treatment paradigm to resemble human caffeine consumption, we provided the direct evidence that chronic caffeine treatment confers neuroprotective effect by blunting a cascade of pathological events leading to α-Syn pathology, including pSer129α-Synrich aggregates, neuroinflammation, and apoptotic neuronal cell death
Removal of protein aggregates such as misfolded mutant A53T α-Syn fibrils can occur via the autophagy-lysosomal pathway and ubiquitin proteasome system (UPS). To explore this possible involvement of UPS in α-Syn fibrils model of PD we examined the effect of caffeine on the level of PSMC3 and proteasome 20S beta 6 protein, as indicator of UPS activity because both are mainly degraded by UPS system
Summary
Parkinson’s disease (PD) is pathologically characterized by selective degeneration of dopaminergic neurons in the midbrain and the presence of intracellular amyloidogenicα-synuclein (α-Syn) inclusions, known as Lewy bodies and Lewy neurites, which progress from the medulla to midbrain and throughout cortical areas. Many recent studies suggested a “prion-like” cell-to-cell transmission of α-Syn as a critical molecular event underlying the spread of α-Syn pathology and disease progression in PD (Masuda-Suzukake et al, 2013; Brundin and Melki, 2017; Goedert et al, 2017). In the absence of an effective treatment for PD, epidemiological and experimental investigations into potential risk factors (including dietary factors) that may allow individuals to decrease their risk for neurodegenerative disorders has become more appealing. A recent meta-analysis of 110 observational studies has firmly established a relationship between increased caffeine consumption and decreased risk of developing PD (Grosso et al, 2017). There are concerns over the failure of recent clinical trials to demonstrate the symptomatic therapeutic benefits in PD patients (Simon et al, 2015; Postuma et al, 2017)
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