Impact of western diet and Pcsk9 on the expression of amyotrophic lateral sclerosis-predisposing genes

Background and Aim: Amyotrophic lateral sclerosis (ALS)is a fatal neurodegenerative disorder characterized by progressive degeneration of motor neurons. Mutations in three genes,C9orf72, SOD1, TARDBP, account for the disease in about 70%of patients with familial ALS. Since cholesterol may play a role in the onset/progression of ALS, the impact of PCSK9, as well as that of different dietary lipid contents, on the expression of genes relevant in ALS and cholesterol metabolism was evaluated in brain and liver.Methods: Six-week-old C57BL/6J WT and PCSK9-KO female mice were fed for 16 weeks either standard chow diet (CD), or Western-type diet (WD). After sacrifice, gene expression in liver and brain was evaluated via qPCR. Results: When comparing dietary treatments, in the liver of both genotypes, WD significantly increased the expression ofSod1, Tardbp and C9orf72, as well as that of Dhcr24, Cyp27a1,Cyp46a1 and Soat1 vs. CD. In the brain, WD did not alter the expression of any of the genes considered. When comparing genotypes, the hepatic expression of Sod1, Tardbp and C9orf72 was comparable in PCSK9-KO and WT when fed the same diet. On WD, increased hepatic expression of Dhcr24, Dhcr7, Msmo1,Hmgcr and Ldlr was observed in PCSK9-KO vs. WT. Conversely,in the brain, PCSK9-KO mice showed increased expression ofC9orf72, Tardbp, Ldlr and Hmgcr, vs. WT when fed the same diet. Conclusions: WD administration increases the expression ofALS-predisposing genes only in the liver but not in the brain in a genotype-independent manner. The lack of PCSK9 consistently results in increased expression of C9orf72 and Tardbp in the brain. Additional studies may shed light on the role of PCSK9in the onset of ALS.