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© 2018 Jensen PH. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License We have recently reported that alpha-synuclein aggregates induce calcium dysregulation by activating the calcium pump, SERCA in the endoplasmic reticulum1. The dysregulation presents as a biphasic change in cytosolic calcium with an initial phase with 20% decreased calcium followed by final phase with increased calcium. These findings are novel with respect to; 1) demonstrating activation of SERCA as a gain-offunction acquired by aggregated alpha-synuclein; 2) demonstrating an initial phase with reduced cytosolic calcium in neurons that experience a build-up of alpha-synuclein aggregates. The initial phase occurs when cells appear morphologically unaffected and precedes the wellknown later phase with increased cytosolic calcium and subsequent cell death. Although the reduction in cytosolic calcium of 20% may appear modest are its short and long-term consequences largely unknown because this phase not previously has been described. However, both the early and late phase of the calcium dysregulation can be antagonized pharmacologically by inhibiting SERCA and this treatment restored the survival of the cells to the level of the control cells not being subject to alpha-synuclein aggregate stress. The interaction between aggregated synuclein and SERCA could be demonstrated in neurons in brain tissue affected by dementia with Lewy bodies supporting that the initial phase with reduced cytosolic calcium is relevant for human pathology. We hypothesize the alpha-synuclein aggregate induced stimulation of SERCA and the early-phase with reduced cytosolic calcium will compromise neurons ability to support their role in normal circuitries, integrated brain functions and ultimately cause symptoms. This phase may exist for prolonged periods before the neurons enters the latephase with increased cytosolic calcium that has been studied according to the original “calcium hypothesis”2,3. Understanding the mechanisms whereby the abnormal activation of SERCA and its down-stream dysregulation of calcium contributes to neuronal dysfunction and eventual cell death holds potential for new symptomatic and disease modifying strategies for synucleinopathies.

Commentary: Alpha-Synuclein Aggregates Cause Calcium Dysregulation by Activating Calcium Pump SERCA