Research Report 2010 - MDC

Structure of the GroupSimone SpulerGroup LeaderProf. Dr. Simone SpulerScientistsPD Dr. Ute ZachariasPD Dr. Hans KnoblauchDr. Verena SchöwelDr. Stephanie AdamsDr. Miriam CarlMuscle Research Unit and ClinicalResearch Group (CRG) 192Simone Spuler directs CRG 192 for skeletal muscle diseases (speaker, Friedrich C. Luft) at theCharité. CRG 192 is home to groups at all Charité campuses; however, much of the researchactivities, including her own research team is located at the ECRC. Within the ECRC, she directsan outpatient clinical for >1000 patients with genetic and acquired skeletal muscle diseases.CRG 192 is in the process of expanding by founding a graduate school (Graduiertenkolleg) fordoctoral and postdoctoral students in conjunction with the University of Paris. Simone Spulerhas focused her attention on dysferlin. The dysferlinopathies encompass a large variety ofneuromuscular diseases characterized by the absence of dysferlin in skeletal muscle and anautosomal recessive mode of inheritance. Three main phenotypes are known, Miyoshimyopathy, limb girdle muscular dystrophy type 2B, and distal myopathy with anterior tibialonset.Dysferlin is a large protein located at the sarcolemmaand is involved in membrane repair after microinjury, aphysiological consequence of normal muscle activity.Patients with mutations in the dysferlin gene experienceprogressive muscle weakness in early adulthoodleading to loss of ambulation within 10-15 years. Soonafter the dysferlin gene was discovered in 1998, inflammatorychanges were observed to be an intrinsic part ofthe disease spectrum in dysferlinopathies. The Spulerlaboratory was the first to demonstrate involvement ofthe immune system. They observed that the complementinhibitory factor CD 55 is selectively downregulatedon dysferlin-deficient skeletal muscle leading toincreased vulnerability to complement attacks.Modulation of the complement cascade may open atherapeutic strategy.The team was also the first to demonstrate that dysferlinmutations lead to misfolding and aggregation ofdysferlin and muscle amyloidosis. In many aspects, dysferlinopathiesresemble other protein misfolding diseasessuch as Alzheimer’s disease and Parkinson’s disease.Dr. Verena Schöwel is working on a strategy to rescuemissense-mutated dysferlin from degradation andrelocating the molecule to the plasma membrane. Dr.Ute Zacharias is investigating the effect of the potentmodulator of skeletal muscle growth, myostatin, ondysferlin-deficient human myotubes. These efforts areleading to novel treatments to relocate the availableprotein. An effort is underway to apply this new knowledgeto in vivo models.Muscular dystrophies are closely related to generalizeddisturbances in metabolism. Years ago, muscular dystrophieswere considered to be endocrinological diseases.This aspect was later neglected due to the enormousprogress in visualization techniques, genetictools, and molecular biology. The structural abnormalitiesof skeletal muscle disorders were described andcategorized. Furthermore, many new genes were identifiedthat cause myopathies once mutated. However, the208 The Experimental and Clinical Research Center