• Weijing Qi, Lina Yan, Yaling Liu, Xiaomeng Zhou, Rui Li, Yafei Wang, Lin Bai, Juan Chen, and Xiangyu Nie.
• Key Laboratory of Neurology of Hebei Province, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, PR China.
• Neuroscience. 2019 Jun 15; 409: 130-141.

AbstractAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by selective loss of motor neurons. Statins are widely used as cholesterol-lowering drugs and significantly reduce the risk of cardiovascular and cerebrovascular diseases. Increasing evidence indicates the protective effects of statins against certain neurodegenerative diseases. However, in ALS, many studies have found that statins might accelerate disease progression and shorten survival, although the exact mechanism is unclear. In the present study, we investigated the effect of simvastatin on NSC34cells stably transfected with the G93A mutation in human SOD1 (NSC34-hSOD1G93A cells), a recognized in vitro model of ALS. Our results showed that simvastatin caused a decrease in cell viability and the accumulation of autophagic vacuoles with elevated levels of LC3 II/I and P62 in NSC34-hSOD1G93A cells. Conversely, these outcomes were completely reversed by co-incubation with mevalonate, farnesyl pyrophosphate (FPP) or geranylgeranyl pyrophosphate (GGPP) but not cholesterol. In addition, inhibition of geranylgeranyl transferase I by GGTI-286 led to similar alterations in cell viability and autophagic marker levels. These results indicated that the cytotoxic effect of simvastatin on NSC34-hSOD1G93A cells might be due to the aggravation of autophagic flux impairment through the inhibition of GGPP synthesis.Copyright © 2019 IBRO. Published by Elsevier Ltd. All rights reserved.

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