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.


Relevant publications

Smith, IC, Chakraborty, S, Bourque, PR, Sampaio, ML, Melkus, G, Lochmüller, H et al.. Emerging and established biomarkers of oculopharyngeal muscular dystrophy. Neuromuscul Disord. 2023.33 (11)824-834 PMID:37926637

O'Connor, K, Spendiff, S, Lochmüller, H, Horvath, R. Mitochondrial Mutations Can Alter Neuromuscular Transmission in Congenital Myasthenic Syndrome and Mitochondrial Disease. Int J Mol Sci. 2023.24 (10) PMID:37239850

Pugliese, A, Holland, SH, Rodolico, C, Lochmüller, H, Spendiff, S. Presynaptic Congenital Myasthenic Syndromes: Understanding Clinical Phenotypes through In vivo Models. J Neuromuscul Dis. 2023.10 (5)731-759 PMID:37212067

Hentschel, A, Meyer, N, Kohlschmidt, N, Groß, C, Sickmann, A, Schara-Schmidt, U et al.. A Homozygous PPP1R21 Splice Variant Associated with Severe Developmental Delay, Absence of Speech, and Muscle Weakness Leads to Activated Proteasome Function. Mol Neurobiol. 2023.60 (5)2602-2618 PMID:36692708

Hathazi, D, Cox, D, D'Amico, A, Tasca, G, Charlton, R, Carlier, RY et al.. INPP5K and SIL1 associated pathologies with overlapping clinical phenotypes converge through dysregulation of PHGDH. Brain. 2021.144 (8)2427-2442 PMID:33792664

Spendiff, S, Howarth, R, McMacken, G, Davey, T, Quinlan, K, O'Connor, E et al.. Modulation of the Acetylcholine Receptor Clustering Pathway Improves Neuromuscular Junction Structure and Muscle Strength in a Mouse Model of Congenital Myasthenic Syndrome. Front Mol Neurosci. 2020.13 594220 PMID:33390901

McMacken, G, Whittaker, RG, Charlton, R, Barresi, R, Lochmüller, H, Horvath, R et al.. Inherited neuropathies with predominant upper limb involvement: genetic heterogeneity and overlapping pathologies. Eur J Neurol. 2021.28 (1)297-304 PMID:32909314

Donkervoort, S, Mohassel, P, Laugwitz, L, Zaki, MS, Kamsteeg, EJ, Maroofian, R et al.. Biallelic loss of function variants in SYT2 cause a treatable congenital onset presynaptic myasthenic syndrome. Am J Med Genet A. 2020.182 (10)2272-2283 PMID:32776697

Töpf, A, Oktay, Y, Balaraju, S, Yilmaz, E, Sonmezler, E, Yis, U et al.. Severe neurodevelopmental disease caused by a homozygous TLK2 variant. Eur J Hum Genet. 2020.28 (3)383-387 PMID:31558842

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