Synaptopodin regulates the actin-bundling activity of α-actinin in an isoform-specific manner

Asanuma, Katsuhiko; Kim, Kwanghee; Oh, Jun; Giardino, Laura; Chabanis, Sophie; Faul, Christian; Reiser, Jochen; Mündel, Peter

doi:10.1172/jci200523371

Cited by 259 publications

(266 citation statements)

References 31 publications

Supporting

Mentioning

254

Contrasting

Order By: Relevance

“…Transient transfection of podocytes and HEK293 cells (American Type Culture Collection, Manassas, VA) was done as described previously (54). GFP fusion proteins were analyzed by direct fluorescence microscopy in living cells or after fixation and double labeling immunocytochemistry (54).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Nuclear relocation of the nephrin and CD2AP-binding protein dendrin promotes apoptosis of podocytes

Asanuma

Campbell

Kim

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

126

View full text Add to dashboard Cite

Kidney podocytes and their slit diaphragms (SDs) form the final barrier to urinary protein loss. There is mounting evidence that SD proteins also participate in intracellular signaling pathways. The SD protein nephrin serves as a component of a signaling complex that directly links podocyte junctional integrity to actin cytoskeletal dynamics. Another SD protein, CD2-associated protein (CD2AP), is an adaptor molecule involved in podocyte homeostasis that can repress proapoptotic TGF-␤ signaling in podocytes. Here we show that dendrin, a protein originally identified in telencephalic dendrites, is a constituent of the SD complex, where it directly binds to nephrin and CD2AP. In experimental glomerulonephritis, dendrin relocates from the SD to the nucleus of injured podocytes. High-dose, proapoptotic TGF-␤1 directly promotes the nuclear import of dendrin, and nuclear dendrin enhances both staurosporine-and TGF-␤1-mediated apoptosis. In summary, our results identify dendrin as an SD protein with proapoptotic signaling properties that accumulates in the podocyte nucleus in response to glomerular injury and provides a molecular target to tackle proteinuric kidney diseases. Nuclear relocation of dendrin may provide a mechanism whereby changes in SD integrity could translate into alterations of podocyte survival under pathological conditions. glomerular injury ͉ proapoptotic signaling ͉ TGF-␤ signaling ͉ slit diaphragm G lomerular podocytes serve as the final barrier to urinary protein loss by the formation and maintenance of podocyte foot processes (FP) and the interposed slit diaphragm (SD) (1). All forms of nephrotic syndrome are characterized by abnormalities in podocytes, including retraction (effacement) of podocyte FP and/or molecular reorganization of the SD (1). The discovery of several podocyte proteins and their mutation analysis, including nephrin (2), CD2-associated protein (CD2AP) (3), ␣-actinin-4 (4), podocin (5), TRPC6 (6, 7), and neph1 (8), have shed light on the pathogenesis of proteinuria and emphasized the critical role of the podocyte and the SD in maintaining the function of the glomerular filtration barrier. At the cytoplasmic insertion site of the SD, ZO-1 (9), ␣-, ␤-, ␥-catenins (10), podocin (11), and CD2AP (3) are present. In nephrotic syndrome, the normal podocyte substructure is lost, with effacement of podocyte FP, proteinuria (1), as well as altered phosphorylation of ZO-1 (12) and nephrin (13,14).Dendrin is a proline-rich protein of unknown function that was originally identified in telencephalic dendrites of sleep-deprived rats (15). In the brain, two protein variants (81 kDa, 89 kDa) were identified in cytosolic and membranous protein fractions (15). More recently, KIBRA, a WW domain-containing protein, was identified as a dendrin-interacting protein, but the functional relevance of this interaction remains to be established (16). Here we show that dendrin is a component of the SD complex. We further show that dendrin relocates to the nucleus of injured podocytes in a murine model of cr...

show abstract

Section: Methodsmentioning

confidence: 99%

“…SDS/PAGE, Western blotting, coimmunoprecipitation from transfected HEK cells, and endogenous coimmunoprecipitation from isolated glomerular extracts were done as described previously (21,54). GST pulldown studies with GST-dendrin and glomerular protein extracts were done as described previously (21,22).…”

Section: Methodsmentioning

confidence: 99%

Nuclear relocation of the nephrin and CD2AP-binding protein dendrin promotes apoptosis of podocytes

Asanuma

Campbell

Kim

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

126

View full text Add to dashboard Cite

show abstract

“…Recently, the existence of 3 Synpo isoforms, Synpo-long, Synposhort, and Synpo-T, has been described (20). We therefore tested whether CD2AP interacts with all isoforms of Synpo.…”

Section: Introductionmentioning

confidence: 98%

“…Recently generated Synpo -/-mice lack the Synpo-short and Synpo-long expression but still express Synpo-T isoform in podocytes (20). While these mice exhibit neuronal defects, no spontaneous kidney phenotype was detected (20,21 Figure 3A). In the presence of CD2AP haploinsufficiency, however, 58% of Synpo -/-and 29% of Synpo +/-mice developed proteinuria.…”

Section: Introductionmentioning

confidence: 99%

“…There are 3 isoforms of Synpo (Synpo-long, Synpo-short, and Synpo-T) that are generated by alternative RNA splicing (20). Recently generated Synpo -/-mice lack the Synpo-short and Synpo-long expression but still express Synpo-T isoform in podocytes (20). While these mice exhibit neuronal defects, no spontaneous kidney phenotype was detected (20,21 Figure 3A).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Bigenic mouse models of focal segmental glomerulosclerosis involving pairwise interaction of CD2AP, Fyn, and synaptopodin

Huber¹

2006

Journal of Clinical Investigation

143

105

View full text Add to dashboard Cite

Focal segmental glomerulosclerosis (FSGS) is the most common primary glomerular diagnosis resulting in end-stage renal disease. Defects in several podocyte proteins have been implicated in the etiology of FSGS, including podocin, a-actinin-4, CD2-associated protein (CD2AP), and TRPC6. Despite our growing understanding of genes involved in the pathogenesis of focal segmental sclerosis, the vast majority of patients with this disease, even those with a familial linkage, lack a clear genetic diagnosis. Here, we tested whether combinations of genetic heterozygosity (bigenic heterozygosity) that alone do not result in clinical kidney disease could function together to enhance susceptibility to glomerular damage and FSGS. Combinations of Cd2ap heterozygosity and heterozygosity of either synaptopodin (Synpo) or Fyn proto-oncogene (Fyn) but not kin of IRRE like 1 (Neph1) resulted in spontaneous proteinuria and in FSGS-like glomerular damage. These genetic interactions were also reflected at a functional level, as we found that CD2AP associates with Fyn and Synpo but not with Neph1. This demonstrates that bigenic heterozygosity can lead to FSGS and suggests that combined mutations in 2 or multiple podocyte genes may be a common etiology for glomerular disease. IntroductionFocal segmental glomerulosclerosis (FSGS) is a major cause of endstage renal disease and is increasing in frequency (1). The structure affected in FSGS is the kidney glomerulus, which is composed of capillaries that are involved in the filtration of blood. The diagnosis of FSGS is based on the clinical findings of proteinuria and specific histopathological changes, with areas of glomerular sclerosis and glomerular tuft collapse that are both focal and segmental. Focal refers to the finding that not all glomeruli are affected, and segmental indicates that only a portion of the affected glomerulus is sclerosed. While the etiology of most cases of FSGS is unknown, the heterogeneous nature of these histologic changes suggests that a combination of different factors is involved, including genetic and environmental influences (2, 3).The podocyte, the visceral epithelial cell of the glomerulus, has taken center stage in research on the pathogenesis of FSGS. Genetic studies in both human and mouse reveal that the development of FSGS is initiated by podocyte dysfunction (2). In humans, mutations of the podocyte-specific gene nephrosis 2 homolog, podocin (Nphs2) (encoding podocin) (4), the more ubiquitously expressed cytoskeletal protein a-actinin-4 (5), and the ion channel protein TRPC6 (6, 7) have been shown to impair podocyte function and to cause an inherited form of FSGS. Mouse studies demonstrate that the complete absence of either podocin (8) or a-actinin-4 (9) results not in FSGS but in a severe podocyte dysfunction leading

show abstract

Acetylated tau in Alzheimer's disease: An instigator of synaptic dysfunction underlying memory loss

Tracy

Gan

2017

BioEssays

View full text Add to dashboard Cite

Summary Pathogenesis in tauopathies involves the accumulation of tau in the brain and progressive synapse loss accompanied by cognitive decline. Pathological tau is found at synapses, and it promotes synaptic dysfunction and memory deficits. The specific role of toxic tau in disrupting the molecular networks that regulate synaptic strength has been elusive. A novel mechanistic link between tau toxicity and synaptic plasticity involves the acetylation of two lysines on tau, K274 and K281, which are associated with dementia in Alzheimer’s disease (AD). We propose that an increase in tau acetylated on these lysines blocks the expression of long-term potentiation at hippocampal synapses leading to impaired memory in AD. Acetylated tau could inhibit the activity-dependent recruitment of postsynaptic AMPA-type glutamate receptors required for plasticity by interfering with the postsynaptic localization of KIBRA, a memory-associated protein. Strategies that reduce the acetylation of tau may lead to effective treatments for cognitive decline in AD.

show abstract

Synaptopodin regulates the actin-bundling activity of α-actinin in an isoform-specific manner

Cited by 259 publications

References 31 publications

Nuclear relocation of the nephrin and CD2AP-binding protein dendrin promotes apoptosis of podocytes

Nuclear relocation of the nephrin and CD2AP-binding protein dendrin promotes apoptosis of podocytes

Bigenic mouse models of focal segmental glomerulosclerosis involving pairwise interaction of CD2AP, Fyn, and synaptopodin

Acetylated tau in Alzheimer's disease: An instigator of synaptic dysfunction underlying memory loss

Contact Info

Product

Resources

About