Effects of Prolonged Intermittent Fasting Model on Energy Metabolism and Mitochondrial Functions in Neurons.

Background: Calorie restriction (CR) during daily nutrition has been shown to affect the prognosis of many chronic diseases such as metabolic syndrome, diabetes, and aging. As an alternative nutrition model, prolonged intermittent fasting (PF) in humans is defined by the absence of food for more than 12 h. In our previous human studies, CR and PF models were compared and it was concluded that the two models might have differences in signal transduction mechanisms. We have investigated the effects of these models on neurons at the molecular level in this study. Methods: Neurons (SH-SY5Y) were incubated with normal medium (N), calorie-restricted medium (CR), fasting medium (PF), and glucose-free medium (G0) for 16 h. Simultaneously, ketone (beta-hydroxybutyrate; bOHB) was added to other experiment flasks containing the same media. Concentrations of lactate, lactate dehydrogenase (LDH), bOHB, and glucose were measured to demonstrate the changes in the energy metabolism together with the mitochondrial functions of cells. Citrate synthase activity and flow cytometric mitochondrial functions were investigated. Results: At the end of incubations, lactate and LDH levels were decreased and mitochondrial activity was increased in all ketone-added groups (P < .01) regardless of the glucose concentration in the environment. In the fasting model, these differences were more prominent. Conclusion: Our results demonstrated that neurons use ketones regardless of the amount of glucose, and bOHB-treated cells had positive changes in mitochondrial function. We conclude that the presence of bOHB might reverse neuron damage and that exogenous ketone treatment may be beneficial in the treatment of neurological diseases in the future.

HPCA confirmed as a genetic cause of DYT2-like dystonia phenotype.

BACKGROUND: HPCA (hippocalcin) is one of the underlying genetic causes of autosomal-recessively inherited forms of dystonia. Here, we describe two consanguineous Turkish DYT-HPCA families carrying the novel HPCA mutations. METHODS: After detailed clinical and neurological examination, whole-exome sequencing was performed. RESULTS: Whole-exome sequencing analysis revealed two homozygous novel truncating mutations (p.W103* and p.P10PfsTer80) in the HPCA gene in two unrelated Turkish dystonia families presenting with complex dystonia. CONCLUSIONS: After identification of HPCA as a genetic cause of DYT-HPCA-like dystonia by Charlesworth et al, this is the second report in the scientific literature that describes dystonia families harboring HPCA mutations. Our findings confirm that HPCA leads to recessively inherited dystonia. © 2018 International Parkinson and Movement Disorder Society.

Role of LRRK2 and SNCA in autosomal dominant Parkinson's disease in Turkey.

INTRODUCTION: Mutations in the LRRK2 and alpha-synuclein (SNCA) genes are well-established causes of autosomal dominant Parkinson's disease (PD). However, their frequency differs widely between ethnic groups. Only three studies have screened all coding regions of LRRK2 and SNCA in European samples so far. In Turkey, the role of LRRK2 in Parkinson's disease has been studied fragmentarily, and the incidence of SNCA copy number variations is unknown. The purpose of this study is to determine the frequency of LRRK2 and SNCA mutations in autosomal dominant PD in Turkey. METHODS: We performed Sanger sequencing of all coding LRRK2 and SNCA exons in a sample of 91 patients with Parkinsonism. Copy number variations in SNCA, PRKN, PINK1, DJ1 and ATP13A2 were assessed using the MLPA method. All patients had a positive family history compatible with autosomal dominant inheritance. RESULTS: Known mutations in LRRK2 and SNCA were found in 3.3% of cases: one patient harbored the LRRK2 G2019S mutation, and two patients carried a SNCA gene duplication. Furthermore, we found a heterozygous deletion of PRKN exon 2 in one patient, and four rare coding variants of unknown significance (LRRK2: A211V, R1067Q, T2494I; SNCA: T72T). Genetic testing in one affected family identified the LRRK2 R1067Q variant as a possibly pathogenic substitution. CONCLUSION: Point mutations in LRRK2 and SNCA are a rare cause of autosomal dominant PD in Turkey. However, copy number variations should be considered. The unclassified variants, especially LRRK2 R1067Q, demand further investigation.

Mutations in TYROBP are not a common cause of dementia in a Turkish cohort.

Mutations in TYROBP and TREM2 have been shown to cause polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy. Recently, variants in TREM2 were also associated with frontotemporal dementia and Alzheimer's disease. Given the functional proximity between these 2 genes, we investigated the genetic variation of TYROBP in a Turkish cohort of 103 dementia patients. No mutations or copy number variants predicted to be pathogenic were identified. These results indicate that mutations in TYROBP are not a common cause of dementia in this Turkish cohort.