Identification of pathomechanisms

For many neuromuscular diseases, the genetic cause is known, and the challenge is then to translate these gene discoveries into patient-tailored treatments. To achieve this, disease-relevant models are essential to support characterization of the disease, unravel the pathogenic mechanisms, identify new therapeutic targets for intervention, and perform preclinical testing where potential therapeutics/targets are identified. The full elucidation of pathomechanisms is crucial not only to fully understand the molecular causes of the diseases but also to define starting points for testing of potential therapeutic interventions. To this end, our lab generates animal models and makes use of patient-derived material, often in close collaboration with other international research groups, using techniques including cell biology approaches, functional studies, genomics, transcriptomics, proteomics and immunological techniques such as immunofluorescence studies. The development of animal models (mouse and zebrafish) for a variety of neuromuscular diseases has enabled us to study the phenotypic consequences of gene knock-down and associated pathomechanisms in vivo, which not only allows validation of gene discoveries but also provides insights towards ways of correcting the defect and thus towards therapeutic targets.

zebrafish

Relevant publications

Issop, Y, Hathazi, D, Khan, MM, Rudolf, R, Weis, J, Spendiff, S et al.. GFPT1 deficiency in muscle leads to myasthenia and myopathy in mice. Hum. Mol. Genet. 2018.27 (18)3218-3232 PMID:29905857

O'Connor, E, Phan, V, Cordts, I, Cairns, G, Hettwer, S, Cox, D et al.. MYO9A deficiency in motor neurons is associated with reduced neuromuscular agrin secretion. Hum. Mol. Genet. 2018.27 (8)1434-1446 PMID:29462312

O'Connor, E, Töpf, A, Zahedi, RP, Spendiff, S, Cox, D, Roos, A et al.. Clinical and research strategies for limb-girdle congenital myasthenic syndromes. Ann. N. Y. Acad. Sci. 2018.1412 (1)102-112 PMID:29315608

Nicole, S, Azuma, Y, Bauché, S, Eymard, B, Lochmüller, H, Slater, C et al.. Congenital Myasthenic Syndromes or Inherited Disorders of Neuromuscular Transmission: Recent Discoveries and Open Questions. J Neuromuscul Dis. 2017.4 (4)269-284 PMID:29125502

Unger, A, Beckendorf, L, Böhme, P, Kley, R, von Frieling-Salewsky, M, Lochmüller, H et al.. Translocation of molecular chaperones to the titin springs is common in skeletal myopathy patients and affects sarcomere function. Acta Neuropathol Commun. 2017.5 (1)72 PMID:28915917

Carr, SJ, Zahedi, RP, Lochmüller, H, Roos, A. Mass spectrometry-based protein analysis to unravel the tissue pathophysiology in Duchenne muscular dystrophy. Proteomics Clin Appl. 2018.12 (2) PMID:28631898

Wiessner, M, Roos, A, Munn, CJ, Viswanathan, R, Whyte, T, Cox, D et al.. Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment. Am. J. Hum. Genet. 2017.100 (3)523-536 PMID:28190456

Jørgensen, LH, Jepsen, PL, Boysen, A, Dalgaard, LB, Hvid, LG, Ørtenblad, N et al.. SPARC Interacts with Actin in Skeletal Muscle in Vitro and in Vivo. Am. J. Pathol. 2017.187 (2)457-474 PMID:27908613

Meng, J, Counsell, JR, Reza, M, Laval, SH, Danos, O, Thrasher, A et al.. Autologous skeletal muscle derived cells expressing a novel functional dystrophin provide a potential therapy for Duchenne Muscular Dystrophy. Sci Rep. 2016.6 19750 PMID:26813695

Klymiuk, N, Blutke, A, Graf, A, Krause, S, Burkhardt, K, Wuensch, A et al.. Dystrophin-deficient pigs provide new insights into the hierarchy of physiological derangements of dystrophic muscle. Hum. Mol. Genet. 2013.22 (21)4368-82 PMID:23784375