Parkinson’s Disease And Neuronal Activity: What Is The Connection?
Using in vitro and in vivo Parkinson’s disease models based on α-synuclein preformed fibrils injection, a research group in Japan (Jun Ueda, Norihito Uemura, and Ryosuke Takahashi) have found that perampanel, an antiepileptic drug, inhibited the propagation of α-synuclein pathology in Parkinson’s disease models (J Ueda et al. Movement Disorders, 2021). These results indicate that suppression of neuronal activity with perampanel could represent a new therapeutic strategy for Parkinson’s disease.
Parkinson’s disease is pathologically characterized by the presence of Lewy bodies composed of misfolded α-synuclein. Although Parkinson’s disease patients experience not only motor symptoms but also nonmotor symptoms, only symptomatic therapies are available for Parkinson’s disease; there is no therapy that inhibits or even slows down the disease progression. It is widely believed that prion-like propagation of abnormal α-synuclein pathology plays a crucial role in Parkinson’s disease. In this scenario, the misfolded α-synuclein works as a template to recruit endogenous normal α-synuclein to the misfolded α-synuclein aggregates in neurons. Then, the misfolded α-synuclein is released into the extracellular space and taken up by adjacent neurons, followed by further α-synuclein misfolding and aggregation in these neurons. This cycle triggers the intercellular propagation of abnormal α-synuclein pathology.
Neurons exhibit electrical activity due to influx and efflux of ions. Increased neuronal activity was observed in the substantia nigra pars reticulata and the globus pallidus internus of Parkinson’s disease models, but the connection between the neuronal activity and the propagation of α-synuclein pathology in Parkinson’s disease remains unclear. Recently, experimental models of Alzheimer’s disease, one of the most common neurodegenerative diseases, suggested that the propagation of tau was affected by neuronal activity, which inspired us to investigate the efficacy of modulating neuronal activity against the propagation of α-synuclein. Moreover, α-synuclein propagation is proposed to occur via various mechanisms of action, such as exocytosis, tunneling-nanotube, and endocytosis. We focused on endocytosis, especially, macropinocytosis. Macropinocytosis is a type of fluid phase endocytosis, characterized by the formation of large endocytic vesicles termed macropinosomes. Could neuronal activity modulate endocytosis? The answer is “Yes”. Activity dependent-bulk endocytosis, which has striking similarities with macropinocytosis, is triggered by elevated neuronal activity and continues only during the stimulation. However, whether macropinocytosis also could be affected by neuronal activity has yet to be shown.
Perampanel is an AMPA-type glutamate receptor antagonist, and inhibits neuronal activity by blocking AMPA receptor-induced sodium and calcium-influx into neurons. We speculated that inhibition of neuronal activity with perampanel attenuated the propagation of α-synuclein pathology in Parkinson’s disease models. We clarified two important points by experiment using perampanel.
1. Perampanel inhibited the propagation of α-synuclein pathology by inhibiting neuronal uptake of α-synuclein preformed fibrils.
2. Neuronal uptake of α-synuclein preformed fibrils was caused via macropinocytosis, which occurred in a neuronal activity-dependent manner.
Although further studies are needed to elucidate the efficacy of perampanel against the interneuronal propagation of α-synuclein pathology, our study elucidated the surprising and interesting connection between Parkinson’s disease and neuronal activity. We are currently trying to translate this finding to an innovative disease-modifying therapy of Parkinson’s disease.
Jun Ueda, MD, PhD, and Ryosuke Takahashi, MD, PhD from the Department of Neurology, Kyoto University Graduate School of Medicine. They attended/presented past WPC Congresses. Professor Takahashi is a member of the WPC Board of Directors.
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