Grażyna Dębska‐Vielhaber

Otto-von-Guericke University Magdeburg

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Stefan Vielhaber

Otto-von-Guericke University Magdeburg

Stefanie Schreiber

Otto-von-Guericke University Magdeburg

Wolfram S. Kunz

Heidelberg University

Susanne Petri

Medizinische Hochschule Hannover

Judith Machts

German Center for Neurodegenerative Diseases

Reinhard Dengler

Medizinische Hochschule Hannover

Frank N. Gellerich

Otto-von-Guericke University Magdeburg

Frank Schreiber

Otto-von-Guericke University Magdeburg

Peter J. Nestor

Mater Health Services

Zemfira Gizatullina

Otto-von-Guericke University Magdeburg

Cooperative Institutions

Otto-von-Guericke University Magdeburg

University Hospital Magdeburg

German Center for Neurodegenerative Diseases

Leibniz Institute for Neurobiology

Center for Behavioral Brain Sciences

Polish Academy of Sciences

University of Bonn

Instytut Biologii Doświadczalnej im. Marcelego Nenckiego

Klinikum Magdeburg

Medizinische Hochschule Hannover

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V14. Complementary use of central and peripheral non-invasive imaging to distinguish between subtypes in amyotrophic lateral sclerosis

Clinical Neurophysiology (2015)

S. Abdulla Karen Lowe Stefanie Schreiber Jörn Kaufmann Grażyna Dębska‐Vielhaber

Upper motor neuron

Corticospinal tract

Cerebral peduncle

10.1016/j.clinph.2015.04.092

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Metabolic progression markers of neurodegeneration in the transgenic G93A‐SOD1 mouse model of amyotrophic lateral sclerosis

European Journal of Neuroscience (2007)

Heiko G. Niessen Grażyna Dębska‐Vielhaber Kerstin Sander Frank Angenstein Albert C. Ludolph

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motor neurons. Visualizing corresponding metabolic changes in the brain of patients with ALS with proton magnetic resonance spectroscopy ((1)H-MRS) may provide surrogate markers for an early disease detection, for monitoring the progression and for evaluating a treatment response. The primary objective of our study was to evaluate whether modifications in MR metabolite levels occur before clinical disease onset, and whether these changes are directly linked to a distinct spatial progression pattern in the CNS. Therefore, age-dependent alterations in the cerebral and spinal metabolic profile in the mouse model of ALS overexpressing the mutated human G93A-superoxide dismutase 1 (G93A-SOD1) were determined by high-resolution MRS of tissue extracts at 14.1 Tesla. Both non-transgenic mice (control mice) and transgenic mice overexpressing the non-mutated human SOD1 (tg-SOD1) served as controls. In the spinal cord of G93A-SOD1 mice significantly decreased levels of N-acetyl aspartate were already detected 34 days postpartum, i.e. about 60 days before the average disease onset caused by motor neuron decline. In addition, glutamine and gamma-aminobutyric acid concentrations were significantly diminished at Day 75, which is still in the presymptomatic phase of the disease. These metabolic changes were further progressive in the course of the disease and started to involve the brainstem at Day 75. Overall, high-resolution (1)H-MRS allows a sensitive spatial and temporal metabolite profiling in the presymptomatic phase of ALS even before significant neuronal cell loss occurs.

10.1111/j.1460-9568.2007.05415.x

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Distinction of sporadic and familial forms of ALS based on mitochondrial characteristics

The FASEB Journal (2018)

Jarosław Walczak Grażyna Dębska‐Vielhaber Stefan Vielhaber Jędrzej Szymański Agata Charzyńska

Bioenergetic failure, oxidative stress, and changes in mitochondrial morphology are common pathologic hallmarks of amyotrophic lateral sclerosis (ALS) in several cellular and animal models. Disturbed mitochondrial physiology has serious consequences for proper functioning of the cell, leading to the chronic mitochondrial stress. Mitochondria, being in the center of cellular metabolism, play a pivotal role in adaptation to stress conditions. We found that mitochondrial dysfunction and adaptation processes differ in primary fibroblasts derived from patients diagnosed with either sporadic or familial forms of ALS. The evaluation of mitochondrial parameters such as the mitochondrial membrane potential, the oxygen consumption rate, the activity and levels of respiratory chain complexes, and the levels of ATP, reactive oxygen species, and Ca2+ show that the bioenergetic properties of mitochondria are different in sporadic ALS, familial ALS, and control groups. Comparative statistical analysis of the data set (with use of principal component analysis and support vector machine) identifies and distinguishes 3 separate groups despite the small number of investigated cell lines and high variability in measured parameters. These findings could be a first step in development of a new tool for predicting sporadic and familial forms of ALS and could contribute to knowledge of its pathophysiology.—Walczak, J., Dębska-Vielhaber, G., Vielhaber, S., Szymański, J., Charzyńska, A., Duszyński, J., Szczepanowska, J. Distinction of sporadic and familial forms of ALS based on mitochondrial characteristics. FASEB J. 33, 4388–4403 (2019). www.fasebj.org

Bioenergetics

Mitochondrial disease

10.1096/fj.201801843r

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Nervensonographische Textur- und Grauwertmarker bei ALS

Nervenheilkunde (2019)

Stefanie Schreiber Frank Schreiber Cornelia Garz Grażyna Dębska‐Vielhaber Anne Assmann

Ultraschallstudien bei ALS fokussieren vorwiegend auf Veränderungen der Nervenquerschnittsflächen (CSA), während die nervale Binnenstruktur sonographisch nicht systematisch untersucht wurde.

10.1055/s-0039-1684977

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Knockout of cyclophilin D in Ppif−/− mice increases stability of brain mitochondria against Ca2+ stress

Archives of Biochemistry and Biophysics (2015)

T. M. Gainutdinov Jeffery D. Molkentin Detlef Siemen Mirjam Ziemer Grażyna Dębska‐Vielhaber

Cyclophilin

Mitochondrial matrix

10.1016/j.abb.2015.05.009

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Peripheral nerve ultrasound in amyotrophic lateral sclerosis phenotypes

Muscle & Nerve (2014)

Stefanie Schreiber Susanne Abdulla Grażyna Dębska‐Vielhaber Judith Machts Verena Dannhardt‐Stieger

In this study we sought to determine the cross-sectional area (CSA) of peripheral nerves in patients with distinct subtypes of amyotrophic lateral sclerosis (ALS).Ulnar and median nerve ultrasound was performed in 78 ALS patients [classic, n = 21; upper motor neuron dominant (UMND), n = 14; lower motor neuron dominant (LMND), n = 20; bulbar, n = 15; primary lateral sclerosis (PLS), n = 8] and 18 matched healthy controls.Compared with controls, ALS patients had significant, distally pronounced reductions of ulnar CSA (forearm/wrist level) across all disease groups, except for PLS. Median nerve CSA (forearm/wrist level) did not differ between controls and ALS.Ulnar nerve ultrasound in ALS subgroups revealed significant differences in distal CSA values, which suggests it has value as a marker of LMN involvement. Its potential was particularly evident in the UMND and PLS groups, which can be hard to separate clinically, yet their accurate separation has major prognostic implications.

Lower motor neuron

Upper motor neuron

10.1002/mus.24431

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Citations (63)

P37. Various sonographic gray-scale measures of the peripheral nerve differ between ALS and ALS disease mimics

Clinical Neurophysiology (2018)

Stefanie Schreiber Frank Schreiber Cornelia Garz Grażyna Dębska‐Vielhaber Judith Machts

10.1016/j.clinph.2018.04.677

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Quantifying disease progression in amyotrophic lateral sclerosis using peripheral nerve sonography

Muscle & Nerve (2016)

Stefanie Schreiber Verena Dannhardt‐Stieger Dorothea Henkel Grażyna Dębska‐Vielhaber Judith Machts

ABSTRACT Introduction: In this study we investigated whether peripheral nerve sonography could be used as a biomarker to monitor disease progression in amyotrophic lateral sclerosis (ALS). Methods: In 37 patients, ulnar and median nerve cross‐sectional area (CSA) was determined in at least 2 ultrasound sessions; mean follow‐up was 14.5 months. Linear mixed‐effects models were conducted to analyze time effects on CSA. Results: Ulnar nerve CSA declined significantly at a monthly rate of –0.04 mm 2 (forearm) and –0.05 mm 2 (wrist); the decrease was more pronounced when baseline CSA was greater. To detect a 50% treatment effect on ulnar nerve CSA, 332 patients would need to be entered in a hypothetical randomized, controlled clinical trial. Time had no significant impact on median nerve CSA. Conclusions: Distal ulnar nerve ultrasound may be a useful biomarker to monitor disease progression in ALS, especially as hypothetical treatment effects on CSA seem to be detectable in manageable cohort sizes. Muscle Nerve 54 : 391–397, 2016

10.1002/mus.25066

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Citations (43)

Interaction of mitochondrial potassium channels with the permeability transition pore

FEBS Letters (2009)

Yu Cheng Grażyna Dębska‐Vielhaber Detlef Siemen

Three types of potassium channels cooperate with the permeability transition pore (PTP) in the inner mitochondrial membranes of various tissues, mtK (ATP) , mtBK, and mtKv1.3. While the latter two share similarities with their plasma membrane counterparts, mtK (ATP) exhibits considerable differences with the plasma membrane K (ATP) ‐channel. One important function seems to be suppression of release of proapototic substances from mitochondria through the PTP. Open potassium channels tend to keep the PTP closed thus acting as antiapoptotic. Nevertheless, in their mode of action there are considerable differences among them. This review introduces three K + ‐channels and the PTP, and discusses known facts about their interaction.

SK channel

10.1016/j.febslet.2009.12.038

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Citations (35)

Novel Pathogenic Sequence Variation m.5789T>C Causes NARP Syndrome and Promotes Formation of Deletions of the Mitochondrial Genome

Neurology Genetics (2022)

Marius Hippen Gábor Zsurka Viktoriya Peeva Judith Machts Kati Schwiecker

We report the pathogenic sequence variant m.5789T>C in the anticodon stem of the mitochondrial tRNA for cysteine as a novel cause of neuropathy, ataxia, and retinitis pigmentosa (NARP), which is usually associated with pathogenic variants in the MT-ATP6 gene.To address the correlation of oxidative phosphorylation deficiency with mutation loads, we performed genotyping on single laser-dissected skeletal muscle fibers. Stability of the mitochondrial tRNACys was investigated by Northern blotting. Accompanying deletions of the mitochondrial genome were detected by long-range PCR and their breakpoints were determined by sequencing of single-molecule amplicons.The sequence variant m.5789T>C, originating from the patient's mother, decreases the stability of the mitochondrial tRNA for cysteine by disrupting the anticodon stem, which subsequently leads to a combined oxidative phosphorylation deficiency. In parallel, we observed a prominent cluster of low-abundance somatic deletions with breakpoints in the immediate vicinity of the m.5789T>C variant. Strikingly, all deletion-carrying mitochondrial DNA (mtDNA) species, in which the corresponding nucleotide position was not removed, harbored the mutant allele, and none carried the wild-type allele.In addition to providing evidence for the novel association of a tRNA sequence alteration with NARP syndrome, our observations support the hypothesis that single nucleotide changes can lead to increased occurrence of site-specific mtDNA deletions through the formation of an imperfect repeat. This finding might be relevant for understanding mechanisms of deletion generation in the human mitochondrial genome.

Sequence (biology)

10.1212/nxg.0000000000000660

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Citations (3)