Role of dystrophin and utrophin for assembly and function of the dystrophin glycoprotein complex in non-muscle tissue

Haenggi, Tatjana; Fritschy, Jean‐Marc

doi:10.1007/s00018-005-5461-0

Cited by 148 publications

(125 citation statements)

References 226 publications

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“…The expression of non-muscular isoforms of dystrophin demonstrated in the macular densa, mesangial and endothelial cells of the kidney supports this possibility [43,44]. Based on our observation in this small patient cohort, further assessment of kidney function and morphology in animal models of DMD is an exciting area for future research and might shed more insight in the underlying pathophysiology of renal dysfunction in DMD patients.…”

Section: Discussionsupporting

confidence: 68%

Renal function in children and adolescents with Duchenne muscular dystrophy

Braat

Hoste

Waele

et al. 2015

Neuromuscular Disorders

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Improved life expectancy and the need for robust tools to monitor renal safety of emerging new therapies have fueled the interest in renal function in Duchenne muscular dystrophy (DMD) patients. We aimed to establish a methodology to accurately assess their renal function. Twenty DMD patients (5-22 years) were included in this prospective study. After obtaining medical history, all patients underwent a clinical examination, 24-hour ambulatory blood pressure monitoring, ultrasound of the kidneys, direct GFR measurement ( 51 Cr-EDTA, mGFR), complete blood and urine analysis. Seventeen of 20 patients were treated with corticosteroids and 5/20 with angiotensin converting enzyme inhibitor (lisinopril). No patient suffered from urinary tract infections or other renal diseases. Hypertension (systolic or diastolic blood pressure >P95) was found in 9/20 patients (8/9 patients were on steroid treatment) and a non-dipping blood pressure profile in 13/20 subjects (10/13 patients were on steroid treatment). Urinary protein to creatinine ratio was elevated in 17/18 patients, whereas 24-hour urine protein excretion was normal in all subjects. Median interquartile range (IQR) mGFR was 130.4 (29.1) mL/min/1.73 m 2 . Hyperfiltration (mGFR >150 mL/min/1.73 m 2 ) was found in 5/20 patients. Inverse correlation between mGFR and age was observed (R 2 = 0.45, p = 0.001). Serum creatinine based estimated GFR (eGFR) equations overestimated mGFR up to 300%. eGFR based on cystatin C Filler equation was closest to the mGFR (median eGFR (IQR) of 129.5 (39.7) mL/min/1.73 m 2 ). Our study demonstrates a high prevalence of hyperfiltration and hypertension in children and adolescents with DMD. Because the majority of hypertensive patients were under corticosteroid treatment, the iatrogenic cause of hypertension cannot be excluded. Serum or urine creatinine measurements are of no value to evaluate renal function in DMD patients due to the reduced skeletal muscle mass.

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Section: Discussionsupporting

confidence: 68%

Renal function in children and adolescents with Duchenne muscular dystrophy

Braat

Hoste

Waele

et al. 2015

Neuromuscular Disorders

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“…Localization of the DGC by immunofluorescence has been documented in neurons, using antibodies to full-length dystrophin, Dp71, utrophin, α-/β-dystroglycan, dystrobrevin, and syntrophins [82,98]. These studies reveal a systematic colocalization with proteins of the GABAergic PSD in a subset of neurons of cortical areas, including the entire cerebral cortex, hippocampal formation (where Dp71 is selectively present in dentate gyrus granule cells), tectum, and cerebellum.…”

Section: The Dystrophin-glycoprotein Complexmentioning

confidence: 96%

“…The DGC is a transmembrane signaling complex present in striate and cardiac muscle cells, kidney tubular epithelial cells, neurons, and astrocytes, linking the extracellular matrix to the actin cytoskeleton (reviewed in [82][83][84]). The DGC is essential for normal brain development and synaptic function and for maintaining the structural integrity of the sarcolemma.…”

Section: The Dystrophin-glycoprotein Complexmentioning

confidence: 99%

“…In neurons, dystrophin was shown initially to be present in PSD fraction of purified brain membranes [86]. Subsequent studies demonstrated its association with a subset of GABAergic synapses [87,88], where it regulates GABA A R clustering and GABAergic synaptic function, as well as glutamatergic synaptic plasticity (reviewed in [83,82]). In mdx mice, direct involvement of dystrophin in synaptic alterations has been demonstrated by dystrophin rescue experiments, which normalize mIPSC amplitude and frequency, as well as LTP in CA1 pyramidal cells [89,90].…”

Section: The Dystrophin-glycoprotein Complexmentioning

confidence: 99%

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Molecular and functional heterogeneity of GABAergic synapses

Fritschy

Panzanelli

Tyagarajan

2012

Cell. Mol. Life Sci.

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Knowledge of the functional organization of the GABAergic system, the main inhibitory neurotransmitter system, in the CNS has increased remarkably in recent years. In particular, substantial progress has been made in elucidating the molecular mechanisms underlying the formation and plasticity of GABAergic synapses. Evidence available ascribes a key role to the cytoplasmic protein gephyrin to form a postsynaptic scaffold anchoring GABA(A) receptors along with other transmembrane proteins and signaling molecules in the postsynaptic density. However, the mechanisms of gephyrin scaffolding remain elusive, notably because gephyrin can auto-aggregate spontaneously and lacks PDZ protein interaction domains found in a majority of scaffolding proteins. In addition, the structural diversity of GABA(A) receptors, which are pentameric channels encoded by a large family of subunits, has been largely overlooked in these studies. Finally, the role of the dystrophin-glycoprotein complex, present in a subset of GABAergic synapses in cortical structures, remains ill-defined. In this review, we discuss recent results derived mainly from the analysis of mutant mice lacking a specific GABA(A) receptor subtype or a core protein of the GABAergic postsynaptic density (neuroligin-2, collybistin), highlighting the molecular diversity of GABAergic synapses and its relevance for brain plasticity and function. In addition, we discuss the contribution of the dystrophin-glycoprotein complex to the molecular and functional heterogeneity of GABAergic synapses. AbstractKnowledge of the functional organization of the GABAergic system, the main inhibitory neurotransmitter system, in the CNS has increased remarkably in recent years. In particular, substantial progress has been made in elucidating the molecular mechanisms underlying formation and plasticity of GABAergic synapses. Evidence available ascribes a key role to the cytoplasmic protein gephyrin to form a postsynaptic scaffold anchoring GABA A receptors along with other transmembrane proteins and signaling molecules in the postsynaptic density. However, the mechanisms of gephyrin scaffolding remain elusive, notably because gephyrin can auto-aggregate spontaneously and lacks PDZ protein interaction domains found in a majority of scaffolding proteins. In addition, the structural diversity of GABA A receptors, which are pentameric channels encoded by a large family of subunits, has been largely overlooked in these studies. Finally, the role of the dystrophin-glycoprotein complex, present in a subset of GABAergic synapses in cortical structures, remains ill-defined. In this review, we discuss recent results derived mainly from the analysis of mutant mice lacking a specific GABA A receptor subtype or a core protein of the GABAergic postsynaptic density (neuroligin-2, collybistin), highlighting the molecular diversity of GABAergic synapses and its relevance for brain plasticity and function. In addition, we discuss the contribution of the dystrophinglycoprotein complex to the molecular ...

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“…This complex has been extensively investigated in muscle cells, in which it is linked to the extracellular matrix of the sarcolemma, providing structural integrity during contraction. 18 DAPs are also present in the glial endfeet with the short dystrophin Dp71, which is the dystrophin isoform most expressed in the brain, [19][20][21][22] whereas other isoforms, such as Dp140 and the 427 full length, are, respectively, expressed by microvessels and neurons. 19,21,[23][24][25] Moreover, distribution of AQP4 and Kir 4.1 is similar to that of DAPs, 12,26,27 and both proteins interact with a-syntrophin by their postsynaptic density-95, discs large, zonula occludens-1 (PDZ) domain, establishing an important link with actin cytoskeleton.…”

mentioning

confidence: 99%

Glial dystrophin-associated proteins, laminin and agrin, are downregulated in the brain of mdx mouse

Nico

Tamma

Annese

et al. 2010

Laboratory Investigation

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In this study, we investigated the involvement of dystrophin-associated proteins (DAPs) and their relationship with the perivascular basement membrane in the brains of mdx mice and controls at the age of 2 months. We analyzed (1) the expression of glial DAPs a-b-dystroglycan (DG), a-syntrophin, aquaporin-4 (AQP4) water channel, Kir 4.1 and dystrophin isoform (Dp71) by immunocytochemistry, laser confocal microscopy, immunogold electron microscopy, immunoblotting and RT-PCR; (2) the ultrastructure of the basement membrane and expression of laminin and agrin; and (3) the dual immunofluorescence colocalization of AQP4/a-b-DG, and of Kir 4.1/agrin. The following results were observed in mdx brain as compared with controls: (1) a significant reduction in protein content and mRNA expression of DAPs; (2) ultrastructurally, a thickened and discontinuous appearance of the basement membrane and a significant reduction in laminin and agrin; and (3) a molecular rearrangment of a-b-DG, coupled with a parallel loss of agrin and Kir 4.1 on basement membrane and glial endfeet. These data indicate that in mdx brain the deficiency in dystrophin and dystrophin isoform (Dp71) is coupled with a reduction of DAP components, coupled with an altered anchoring to the basement membrane. The blood-brain barrier (BBB) controls the selective exchanges between blood and neuropil by specific molecular and structural features of its vascular and perivascular components, including endothelial cells, pericytes, glial endfeet and basement membrane. 1-3 Glial cells have a key role in the control of BBB development and integrity. They express in a polarized way, on their perivascular endfeet, carrier membranes and channel proteins, including aquaporin-4 (AQP4) water channel and potassium channel Kir 4.1, which are responsible for the water flow rate and spatial K þ buffering control. [4][5][6][7][8][9] In the retina, AQP4 colocalizes with Kir 4.1, 9-11 suggesting a tight cooperation between the water flux and K þ siphoning generated by neuronal activity at the BBB interfaces. Moreover, AQP4 and Kir 4.1 rearrangement has been described in BBB alterations, coupled with cytotoxic edema and K þ -delayed buffering capacity. 12,13 AQP4 has a crucial role in the regulation of the interactions occurring between endothelial and glial cells and between glial cells and the extracellular matrix components. AQP4 is a component of the orthogonal aggregate particles (OAPs), demonstrated by freeze fracturing on the ependimoglial membrane and perivascular glial endfeet, 14 the development of which occurs in parallel with AQP4 glial endfeet expression and BBB maturation. 7 Moreover, OAPs contain AQP4 associated with Kir 4.1 12 and their polarized distribution on the glial endfeet seems to be dependent by the presence of the perivascular basement membrane. 15 AQP4 controls BBB functioning, modifying

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Role of dystrophin and utrophin for assembly and function of the dystrophin glycoprotein complex in non-muscle tissue

Cited by 148 publications

References 226 publications

Renal function in children and adolescents with Duchenne muscular dystrophy

Renal function in children and adolescents with Duchenne muscular dystrophy

Molecular and functional heterogeneity of GABAergic synapses

Glial dystrophin-associated proteins, laminin and agrin, are downregulated in the brain of mdx mouse

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