Ultrastructural localization of B-50/growth-associated protein-43 to anterogradely transported synaptophysin-positive and calcitonin gene-related peptide-negative vesicles in the regenerating rat sciatic nerve

Verkade, Paul; Verkleij, Arie J.; Annaert, Willem; Gispen, W.H.; Oestreicher, A.B.

doi:10.1016/0306-4522(95)00463-7

Cited by 11 publications

(18 citation statements)

References 62 publications

(19 reference statements)

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“…Accumulation of marker proteins for other transport cargos and motor proteins at the ligation sites in WT and K3 nerves was comparable. These included the slow transport marker tubulin (29), synaptic vesicle precursor proteins synaptophysin and synaptotagmin, motor protein kinesin-III (27), and calcitonin generelated peptide (30). Together, this shows that tau specifically impairs the anterograde axonal transport of APP-and THcontaining vesicles and mitochondria, and leaves the transport of other cargos unaffected.…”

Section: Morphological Correlates Of Impaired Axonal Transport In K3 mentioning

confidence: 84%

Parkinsonism and impaired axonal transport in a mouse model of frontotemporal dementia

Ittner

Fath

et al. 2008

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

209

214

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Frontotemporal dementia (FTD) is characterized by cognitive and behavioral changes and, in a significant subset of patients, Parkinsonism. Histopathologically, FTD frequently presents with taucontaining lesions, which in familial cases result from mutations in the MAPT gene encoding tau. Here we present a novel transgenic mouse strain (K3) that expresses human tau carrying the FTD mutation K369I. K3 mice develop a progressive histopathology that is reminiscent of that in human FTD with the K369I mutation. In addition, K3 mice show early-onset memory impairment and amyotrophy in the absence of overt neurodegeneration. Different from our previously generated tau transgenic strains, the K3 mice express the transgene in the substantia nigra (SN) and show an early-onset motor phenotype that reproduces Parkinsonism with tremor, bradykinesia, abnormal gait, and postural instability. Interestingly, motor performance of young, but not old, K3 mice improves upon L-dopa treatment, which bears similarities to Parkinsonism in FTD. The early-onset symptoms in the K3 mice are mechanistically related to selectively impaired anterograde axonal transport of distinct cargos, which precedes the loss of dopaminergic SN neurons that occurs in aged mice. The impaired axonal transport in SN neurons affects, among others, vesicles containing the dopamine-synthesizing enzyme tyrosine hydroxylase. Distinct modes of transport are also impaired in sciatic nerves, which may explain amyotrophy. Together, the K3 mice are a unique model of FTD-associated Parkinsonism, with pathomechanistic implications for the human pathologic process.tau ͉ Alzheimer ͉ transgenic ͉ NFT ͉ memory H ow neuronal dysfunction and cell loss is brought about in neurodegenerative diseases such as Alzheimer disease (AD) and frontotemporal dementia (FTD) is only partially understood. In familial cases of FTD with tau aggregation (i.e., FTDP-17), mutations were identified in the MAPT encoding the microtubule (MT)-associated protein tau (1), and in FTD cases without tau aggregation, they were identified in PGRN encoding progranulin (2, 3). Of the 42 known MAPT mutations, several have been expressed in transgenic mice. The mice reproduce selective aspects of the disease which is, in part, determined by the choice of promoter and tau isoform, inclusion of FTDP-17 mutations, the integration site, and copy number of the transgene (4).In FTD and AD, tau becomes increasingly hyperphosphorylated, i.e., more phosphorylated at physiological sites and, in addition, de novo at pathological sites (5). Hyperphosphorylation detaches tau from MTs, and makes it prone to form filamentous inclusions, including neurofibrillary tangles (NFTs) in AD and FTD, and Pick bodies in Pick disease (PiD) (6-9). However, it is only partly understood how aggregated tau interferes with cellular functions.Here we report a novel transgenic mouse strain that expresses K369I mutant human tau in neurons (K3 mice). This mutation has been identified in a patient with a PiD neuropathology (10). Different from prev...

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Section: Morphological Correlates Of Impaired Axonal Transport In K3 mentioning

confidence: 84%

Parkinsonism and impaired axonal transport in a mouse model of frontotemporal dementia

Ittner

Fath

et al. 2008

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

209

214

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“…Ultrathin (70 nm) sections were immunolabelled as described (Verkade et al, 1995(Verkade et al, , 1996a. In short, the sections were blocked and then incubated overnight with the polyclonal antibodies to B-50/ GAP-43 or polyclonal antibodies to calmodulin.…”

Section: Immunogold Labelling Of Lowicryl Hm20 Embedded Nerve Piecesmentioning

confidence: 99%

“…Previously we have described criteria for the quantitative analysis of the immunolabelling associated with transport vesicles (see Verkade et al, 1996a). We defined that gold particles had to be in or within 20nm of an identifiable vesicular profile (with a clearly visible membrane or clearly distinct content).…”

Section: Quantitation Of Immunolabelmentioning

confidence: 99%

“…Chong et al, 1992) and other growth-associated proteins (Hoffman, 1989) in the affected neurons. B-50/GAP-43 is transported to the growth cone by fast anterograde axonal transport (Skene & Willard, 1981a,b;Kalil & Skene, 1986;Bisby, 1988;Hoffman, 1989;Tetzlaff et al, 1989) attached to small 50nm transport vesicles (Skene & Virag, 1989;Verkade et al, 1996a). B-50/GAP-43 is enriched in axonal sprouts distal to the site of injury (Verhaagen et al, 1986;Tetzlaff et al, 1989), but also in the axons proximal to the crush (Verkade et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

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Ultrastructural evidence for the lack of co-transport of B-50/GAP-43 and calmodulin in myelinated axons of the regenerating rat sciatic nerve

et al. 1996

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Following peripheral nerve injury, neurons respond with synthesis of proteins required for axonal regeneration. Newly synthesized membrane proteins, like B-50/GAP-43, are transported with the fast component of anterograde axonal transport. Structural proteins and calmodulin are transported by the slow component. Since B-50/GAP-43 can bind calmodulin, it has been hypothesised that B-50/GAP-43 may act as a carrier for fast anterograde transport of calmodulin, so that both proteins are delivered rapidly to the distally outgrowing axons ('the fast carrier hypothesis'). We have investigated whether this hypothesis is valid in myelinated axons of the regenerating rat sciatic nerve. Seven days after crush, the nerve was ligated to accumulate fast transported proteins. Nerve pieces were dissected proximal to the ligation and processed for immunofluorescence and quantitative electron microscopy by postembedding single and double immunogold labelling. By light microscopy, we observed a qualitative increase in B-50/GAP-43 immunofluorescence in the axonal element immediately proximal to the nerve ligation (termed 'accumulated') compared to an upstream site (termed 'regenerating') closer to the cell body. The immunofluorescence for calmodulin appeared to be the same at both sites. Using electron microscopy, we observed that organelles had collected at the 'accumulated' site, moreover the density of B-50/GAP-43 immunolabelling was significantly increased compared to the 'regenerating' site, where the axoplasmic structure was undisturbed. The increase in B-50/GAP-43 immunolabelling was largely associated with vesicles. The density of calmodulin immunolabelling was similar at both sites. Approximately 25% of the total B-50/GAP-43 was associated with vesicles of which only 15% also contained labelling for calmodulin. Thus, ligation of the nerve resulted in accumulation of vesicles, including those carrying B-50/GAP-43, largely without calmodulin. Therefore, contrary to 'the fast carrier hypothesis', the bulk of calmodulin is not co-transported with B-50/GAP-43 in myelinated axons of the sciatic nerve.

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“…17 GAP-43 is bound by calmodulin when Ca 2+ levels are low and is released when Ca 2+ levels rise ( Figure 2A and B), 18 suggesting that calmodulin may act as a negative regulator of GAP-43 during periods of low activity in the neurons. 19 One functional outcome of GAP-43 during activity-dependent increases in Ca 2+ levels, when it is not bound by calmodulin, may be the regulation of exocytosis and endocytosis and synaptic vesicle recycling 20 via interactions with synaptophysin, 21,22 SNAP-25, 23,24 and rabaptin-5 ( Figures 1 and 2B). 19,25 When calmodulin dissociates from GAP-43, it is free to interact with CamKII, Ca 2+ /calmodulindependent protein II, leading to phosphorylation of cofilin by LIM kinases and neurite outgrowth.…”

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confidence: 99%

GAP-43 in synaptic plasticity: molecular perspectives

Holahan¹

2015

RRBC

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Abstract:The growth-associated protein, GAP-43 (also known as F1, neuromodulin, B-50), participates in the developmental regulation of axonal growth and neural network formation via protein kinase C-mediated regulation of cytoskeletal elements. Transgenic overexpression of GAP-43 can result in the formation of new synapses, neurite outgrowth, and synaptogenesis after injury. In a number of adult mammalian species, GAP-43 has been implicated in the regulation of synaptic transmission and plasticity, such as long-term potentiation, drug sensitization, and changes in memory processes. This review examines the molecular and biochemical attributes of GAP-43, its distribution in the central nervous system, subcellular localization, role in neurite outgrowth and development, and functions related to plasticity, such as those occurring during long-term potentiation, memory formation, and drug sensitization.

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Ultrastructural localization of B-50/growth-associated protein-43 to anterogradely transported synaptophysin-positive and calcitonin gene-related peptide-negative vesicles in the regenerating rat sciatic nerve

Cited by 11 publications

References 62 publications

Parkinsonism and impaired axonal transport in a mouse model of frontotemporal dementia

Parkinsonism and impaired axonal transport in a mouse model of frontotemporal dementia

Ultrastructural evidence for the lack of co-transport of B-50/GAP-43 and calmodulin in myelinated axons of the regenerating rat sciatic nerve

GAP-43 in synaptic plasticity: molecular perspectives

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