Role of Mitochondrial Dynamics in Neuronal Development: Mechanism for Wolfram Syndrome

• DOI: 10.1371/journal.pbio.1002511
• Publication Date: 2016-07-19T13:38:08Z
• Authors: Michal Cagalinec; Mailis Liiv; Zuzana Hodurova; Miriam Ann Hickey; Annika Vaarmann; Merle Mandel; Akbar Zeb; Vinay Choubey; Malle Kuum; Dzhamilja Safiulina; Eero Vasar; Vladimir Veksler; Allen Kaasik
• Keywords: Wolfram syndrome; Homeostasis; DNAJA3

Deficiency of the protein Wolfram syndrome 1 (WFS1) is associated with multiple neurological and psychiatric abnormalities similar to those observed in pathologies showing alterations mitochondrial dynamics. The aim this study was examine hypothesis that WFS1 deficiency affects neuronal function via abnormalities. We show down-regulation neurons leads dramatic changes dynamics (inhibited fusion, altered trafficking, augmented mitophagy), delaying development. induces endoplasmic reticulum (ER) stress, leading inositol 1,4,5-trisphosphate receptor (IP3R) dysfunction disturbed cytosolic Ca2+ homeostasis, which, turn, alters Importantly, ER impaired dynamics, delayed development are causatively related events because interventions at all these levels improved downstream processes. Our data shed light on mechanisms point out potential therapeutic targets. This work may have broader implications for understanding role neuropsychiatric diseases.