Institute of Biomedicine Anatomy


Institute of Biomedicine Anatomy

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Von Nandelstadh P.,Biomedicum Helsinki | Souymani R.,Institute of Biomedicine Anatomy | Baumann M.,Institute of Biomedicine Anatomy | Carpen O.,Biomedicum Helsinki | Carpen O.,University of Turku
Biochemical Journal | Year: 2011

MFM (myofibrillar myopathies) are caused by mutations in several sarcomeric components, including the Z-disc protein myotilin. The morphological changes typical of MFM include Z-disc alterations and aggregation of dense filamentous sarcomeric material. The causes and mechanisms of protein aggregation in myotilinopathies and other forms of MFM remain unknown, although impaired degradation may explain, in part, the abnormal protein accumulation. In the present paper we have studied the mechanisms regulating myotilin turnover, analysed the consequences of defective myotilin degradation and tested whether disease-causing myotilin mutations result in altered protein turnover. The results indicate that myotilin is a substrate for the Ca 2+-dependent protease calpain and identify two calpain cleavage sites in myotilin by MS. We further show that myotilin is degraded by the proteasome system in transfected COS7 cells and in myotubes, and that disease-causing myotilinopathy mutations result in reduced degradation. Finally, we show that proteolysis-inhibitor- induced reduction in myotilin turnover results in formation of intracellular myotilin and actin-containing aggregates, which resemble those seen in diseased muscle cells. These findings identify for the first time biological differences between wt (wild-type) and mutant myotilin. The present study provides novel information on the pathways controlling myotilin turnover and on the molecular defects associated with MFM. © 2011 Biochemical Society.

Jansen M.,Institute of Biomedicine Anatomy | Jansen M.,Minerva Foundation Institute for Medical Research | Wang W.,Institute of Biomedicine Anatomy | Wang W.,Minerva Foundation Institute for Medical Research | And 7 more authors.
FASEB Journal | Year: 2013

The brain is the most cholesterol-enriched tissue in the body. During brain development, desmosterol, an immediate precursor of cholesterol, transiently accumulates up to 30% of total brain sterols. This massive desmosterol deposition appears to be present in all mammalian species reported so far, including humans, but how it is achieved is not well understood. Here, we propose that desmosterol accumulation in the developing brain may be primarily caused by post-transcriptional repression of 3β-hydroxysterol 24-reductase (DHCR24) by progesterone. Furthermore, distinct properties of desmosterol may serve to increase the membrane active pool of sterols in the brain: desmosterol cannot be hydroxylated to generate 24S-hydroxycholesterol, a brain derived secretory sterol, desmosterol has a reduced propensity to be esterified as compared to cholesterol, and desmosterol may activate LXR to stimulate astrocyte sterol secretion. This regulated accumulation of desmosterol by progesterone- induced suppression of DHCR24 may facilitate the rapid enrichment and distribution of membrane sterols in the developing brain. © FASEB.

Yamamoto Y.,Vitality | Craggs L.,Vitality | Baumann M.,Institute of Biomedicine Anatomy | Kalimo H.,University of Helsinki | Kalaria R.N.,Vitality
Neuropathology and Applied Neurobiology | Year: 2011

Y. Yamamoto, L. Craggs, M. Baumann, H. Kalimo and R. N. Kalaria (2011) Neuropathology and Applied Neurobiology37, 94-113 Molecular genetics and pathology of hereditary small vessel diseases of the brainAdvances in molecular genetics have enabled identification of several monogenic conditions involving small vessels predisposing to ischaemic and haemorrhagic strokes and diffuse white matter disease. With emphasis on cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), we review the molecular pathogenesis of recently characterized disorders including cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), retinal vasculopathy with cerebral leukodystrophy (RVCL) and the Collagen type IV, alpha 1 (COL4A1)-related disorders. CADASIL remains the most common hereditary small vessel disease (SVD) caused by >190 different mutations in the NOTCH3 gene, which encodes a cell-signalling receptor. Mutant NOTCH3 instigates degeneration of vascular smooth muscle cells in small arteries and arterioles leading to recurrent lacunar infarcts. Mutations in the serine protease HTRA1 gene are associated with CARASIL. Aberrant HTRA1 activity results in increased transforming growth factor-β signalling provoking multiple actions including vascular fibrosis and extracellular matrix synthesis. The RVCL disorders characterized by profound retinopathy are associated with mutations in TREX1, which encodes an abundant 3'-5' DNA-specific exonuclease. TREX1 mutations lead to detrimental gain-of-function or insufficient quantities of enzyme. The COL4A1-related disorders are highly variable comprising four major phenotypes with overlapping systemic and central nervous system features including SVD with cerebral haemorrhages in children and adults. Mutant COL4A1 likely disrupts the extracellular matrix resulting in fragile vessel walls. The hereditary SVDs albeit with variable phenotypes demonstrate how effects of different defective genes converge to produce the characteristic arteriopathy and microvascular disintegration leading to vascular cognitive impairment. © 2011 The Authors. Neuropathology and Applied Neurobiology © 2011 British Neuropathological Society.

Turunen S.P.,University of Oulu | Kummu O.,University of Oulu | Harila K.,University of Oulu | Veneskoski M.,University of Oulu | And 4 more authors.
PLoS ONE | Year: 2012

Objective: Increased risk for atherosclerosis is associated with infectious diseases including periodontitis. Natural IgM antibodies recognize pathogen-associated molecular patterns on bacteria, and oxidized lipid and protein epitopes on low-density lipoprotein (LDL) and apoptotic cells. We aimed to identify epitopes on periodontal pathogen Porphyromonas gingivalis recognized by natural IgM binding to malondialdehyde (MDA) modified LDL. Methods and Results: Mouse monoclonal IgM (MDmAb) specific for MDA-LDL recognized epitopes on P. gingivalis on flow cytometry and chemiluminescence immunoassays. Immunization of C57BL/6 mice with P. gingivalis induced IgM, but not IgG, immune response to MDA-LDL and apoptotic cells. Immunization of LDLR -/- mice with P. gingivalis induced IgM, but not IgG, immune response to MDA-LDL and diminished aortic lipid deposition. On Western blot MDmAb bound to P. gingivalis fragments identified as arginine-specific gingipain (Rgp) by mass spectrometry. Recombinant domains of Rgp produced in E. coli were devoid of phosphocholine epitopes but contained epitopes recognized by MDmAb and human serum IgM. Serum IgM levels to P. gingivalis were associated with anti-MDA-LDL levels in humans. Conclusion: Gingipain of P. gingivalis is recognized by natural IgM and shares molecular identity with epitopes on MDA-LDL. These findings suggest a role for natural antibodies in the pathogenesis of two related inflammatory diseases, atherosclerosis and periodontitis. © 2012 Turunen et al.

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