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The Scientific Board of IMPG SAS evaluated as the most significant result of 2016 in the field of international collaboration the work by authors M. Cagalinec, M. Liiv, Z. Hodurova, M.A. Hickey, A. Vaarmann, M. Mandel, A. Zeb, V. Choubey, M. Kuum, D. Safiulina, E. Vasar, V. Veksler, A. Kaasik:
Role of Mitochondrial Dynamics in Neuronal Development: Mechanism for Wolfram Syndrome
Wolfram syndrome (WS) is a genetic disorder characterized by diabetes insipidus, diabetes mellitus, optic atrophy, deafness, and brain atrophy. Brain abnormalities occur at the earliest stage of clinical symptoms, suggesting that Wolfram syndrome has a pronounced impact on early brain development. The majority of Wolfram syndrome cases are caused by mutations in the gene Wolfram syndrome 1 (WFS1), which encodes for a protein Wolframin1 localized to the endoplasmic reticulum (ER) membrane. However, the clinical symptoms of WS resemble mitochondrial disease symptoms, suggesting strong mitochondrial involvement. Here, we demonstrate that deficiency of the gene WFS1 triggers an ER-stress cascade, which impairs the function of the IP3-receptor calcium channel, leading to altered calcium homeostasis. The latter leads to dysregulation of mitochondrial dynamics, as characterized by augmented mitophagy – a selective degradation of mitochondria – and inhibited mitochondrial trafficking and fusion, which results in lower levels of ATP and, thus, delayed neuronal development. These results shed new light on the mechanisms of neuronal abnormalities in WS and point out potential new therapeutic targets. Furthermore, our work may also have broad implications for understanding the role of mitochondrial dynamics in neuropsychiatric diseases.
Signalling pathway leading to delayed neuronal development due to absence of protein Wolframin1. Blue arrows represent time course of the cascade.
Projects:
SASPRO 0063/01/02 “Mitochondria-endoplasmic reticulum functional interplay in Wolfram Syndrome: emerging role for heart and brain protection”
MJD35 “Mitochondrial dynamics in models of neurodegenerative diseases”
PUT771 “Targeting mitochondrial dynamics in transgenic rat model of Alzheimer’s disease with superresolution microscopy”
Publication: CAGALINEC, Michal* – LIIV, Mailis – HODUROVA, Zuzana – HICKEY, Miriam Ann – VAARMANN, Annika – MANDEL, Merle – ZEB, Akbar – CHOUBEY, Vinay – KUUM, Malle – SAFIULINA, Dzhamilja – VASAR, Eero – VEKSLER, Vladimir – KAASIK, Allen. Role of mitochondrial dynamics in neuronal development: Mechanism for Wolfram syndrome. In PLoS Biology, 2016, vol. 14, p. e1002511. (8.668 – IF2015). (2016 – Current Contents). ISSN 1545-7885. Type: ADCA
*MC is a research fellow at IMPG CBs SAS financed through the Marie Curie COFUND programme SASPRO, who arrived from the laboratory of prof. A. Kaasik, University of Tartu, Tartu, Estonia