The Unfolded Protein Response in Models of Human Mutant G93A ALS

Featured Article: The Unfolded Protein Response in Models of Human Mutant G93A Amyotrophic Lateral Sclerosis

Featured article of EJN issue 35-5

The unfolded protein response in models of human mutant G93A amyotrophic lateral sclerosis

T. Prell1 , J. Lautenschläger1 , O.W. Witte1 , M.T. Carri2,3, J. Grosskreutz1
1
Hans-Berger Department of Neurology, Friedrich-Schiller-University Hospital Jena, Erlanger Allee 101, D-07747 Jena, Germany
2
Department of Biology, University of Rome “Tor Vergata”, Rome, Italy
3
Fondazione Santa Lucia IRCCS, Rome, Italy

Figure_1. Click on image to enlarge

Recent studies indicate that endoplasmic reticulum (ER) stress is involved in the pathogenesis of familial and sporadic amyotrophic lateral sclerosis (ALS). ER stress occurs when the ER-mitochondria calcium cycle (ERMCC) is disturbed and misfolded proteins accumulate in the ER. To cope with ER stress, the cell engages the unfolded protein reaction (UPR). While activation of the UPR was shown in some ALS models and tissues, ER stress elements have not been studied directly in motor neurones. Here we investigated the expression of XBP1, ATF6α and phosphorylation of eiF2α and their modulation in mutated SOD1G93A cell and animal models of ALS. Expression of XBP1 and ATF6α mRNA and protein is enhanced in SOD1G93A NSC34 cells. Activation of ATF6α, XBP1 and phosphorylation of eiF2α was detectable in mutated SOD1G93A motor neurones, but not in wild type motor neurones. Treatment with the ER stressor thapsigargin enhanced phosphorylation of eiF2α and expression of  ATF6α, XBP1, and sXBP1 in NSC34 cells and motor neurons in a time dependent manner. The present study thus shows the activated UPR directly in motor neurones which overexpress human pathogenic mutant SOD1G93A, providing evidence that ER stress plays a major role in ALS.

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Commentary

Read the corresponding commentary by Ludo Van Den Bosch


Biographical notes

Tino Prell graduated in 2007 at the University of Magdeburg (Germany) and got his medical doctoral degree in 2009 (citrullination of proteins in schwann cells). During training as a specialist neurologist he became involved in medical attendance of ALS patients. From a clinical point of view he is interested in the molecular pathophysiology of motor neuron diseases. He is focused on protein misfolding and calcium disturbance in the context of the endoplasmic reticulum mitochondria calcium cycle (ERMCC). Working in the NEDIG (Neurodegenerative Diseases Group) at the University Hospital Jena, he is involved in several projects concerning the clinical characteristics, MRI biomarkers and cellular pathophysiology of motor neurone diseases.

 

   Janin Lautenschlaeger studied pharmacy from 2004 to 2009 at the Friedrich-Schiller-University of Jena, Germany. Following her diploma at the clinical pharmacology, she started in the NEDIG (Neurodegenerative Diseases Group) of Julian Grosskreutz her PhD thesis. She is focusing on the analysis of calcium dynamics in motor neurons regarding pathologic features of ALS. Evaluation of the dynamics between the endoplasmic reticulum and mitochondria could give further insights in the ongoing process and may providing new therapeutic principles in motor neuron disease.

 

Maria Teresa Carrì  graduated in 1981 at the University of Rome Sapienza. After her first years as a PhD student, she became involved in projects concerning the structure, mechanisms of action and regulation of the expression of the enzyme SOD1 in eukaryotes. In 1994 she became interested in human SOD1 mutants and amyotrophic lateral sclerosis, a field in which she contributed with more than 50 papers published in International Peer Review Journals. She is also working on the biochemical mechanisms of other neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease, Spinal cerebellar ataxia type 1). At present, she is a Full Professor of Biochemistry at the University of Rome Tor Vergata and Head of the Lab of Neurochemistry at the Fondazione Santa Lucia.

 

   Otto W. Witte is the head and Full Professor of Neurology at the Hans Berger Department of Neurology at the University Hospital Jena. With more than 200 papers published in International Peer Review Journals he is involved in several projects with a special focus on neuronal plasticity after cerebral lesions and the understanding of functional and structural brain connectivity by using advanced MRI techniques.

 

   Julian Grosskreutz finished medical school in 1997 and got his medical doctoral degree in 1999 describing the electrophysiological properties of biopsied human sural nerves. He continued to pursue peripheral nerve excitability studies in vitro and in vivo in Syndey (AU) and Graz (A) while training as a specialist neurologist. From 2001 on he studied on ligand gated ion channels, in particular in AMPA receptors, and AMPAR mediated selective motor neuron death at the Hannover Medical School Hospital with partners in Leuven (BE). Using advanced fluorescent imaging techniques in motor neuron cocultures he developed the model of the ER mitochondria calcium cycle (ERMCC) as key affected pathway in amyotrophic lateral sclerosis. After a fellowship abroad in Sheffield (UK) 2006-2007 he received his Habilitation in 2007 and took up a consultant specialist position and lecturer as head of the neuromuscular unit of the Hans Berger Department of Neurology at the University Hospital Jena. He runs the NEDIG (Neurodegenerative Diseases Group) which serves tertiary care for ALS patients, participates in clinical trials, and studies clinical characteristics, MRI biomarkers and cellular pathophysiology of motor neuron diseases.

 

 


More images from the Authors

Images of three-dimensional cultures of motor neurons, generated from spinal ventral cords of 13-day old wild-type (WT) mouse embryos, as in the article. Click on images to enlarge.

 

SMI32 staining with colored depth coding (red on the top and blue at the bottom of the cell).
MN_SMI32_DAPI_2 Cultures were stained for SMI32 (in gray) and DAPI (in blue).
Cultures were stained for SMI32 (in gray) and DAPI (in blue).
  Cultures stained for SMI32 (in gray) and DAPI (in blue).

 

 

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