The Neuroplastins: Multifunctional Neuronal Adhesion Molecules—Involvement in Behaviour and Disease

Beesley, Philip; Kraus, M.; Parolaro, Nathalie

doi:10.1007/978-1-4614-8090-7_4

Cited by 11 publications

(11 citation statements)

References 108 publications

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“…For example, low levels of neurogranin show a clear correlation with cognitive deficits and aging [ 57 ]. The key role played by neuroplastins in synapse formation and its association with impaired intellectual ability might be indicative for the role of FLNC [ 58 ]. Furthermore, we identified also increased PGAM2 expression levels in the FLNC- and GRN-unique datasets as an additional muscle-specific protein that shows altered expression levels in the brain.…”

Section: Discussionmentioning

confidence: 99%

Investigating the role of filamin C in Belgian patients with frontotemporal dementia linked to GRN deficiency in FTLD-TDP brains

Janssens

Philtjens

Kleinberger

et al. 2015

acta neuropathol commun

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TAR DNA-binding protein 43 (TDP-43) inclusions are pathological hallmarks of patients with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Loss of TDP-43 in zebrafish engenders a severe muscle and vascular phenotype with a concomitant elevation of filamin C (FLNC) levels, an observation confirmed in the frontal cortex of FTLD-TDP patients. Here, we aimed to further assess the contribution of FLNC to frontotemporal dementia (FTD) etiology. We conducted a mutational screening of FLNC in a cohort of 529 unrelated Belgian FTD and FTD-ALS patients, and a control cohort of 920 unrelated and age-matched individuals. Additionally we performed an in-depth characterization of FLNC expression levels in FTD patients and a murine FTD model.In total 68 missense variants were identified of which 19 (MAF < 1 %) were patient-only. Gene burden analysis demonstrated a significant association between the presence of rare variants in FLNC and disease (P = 0.0349, RR = 1.46 [95 % CI 1.03–2.07]). Furthermore, elevated FLNC expression levels, observed previously in FTLD-TDP patients, were mainly attributable to FTD patients with the progranulin (GRN) p.0(IVS1 + 5G > C) loss-of-function mutation. Increased FLNC levels were, to a lesser extent, also identified in a FLNC p.V831I variant carrier and in FTD patients with the p.R159H mutation in valosin-containing protein (VCP). The GRN-associated increase of FLNC was confirmed in the frontal cortex of aged Grn knockout mice starting at 16–18 months of age. Combined quantitative proteomic and bioinformatic analyses of the frontal cortex of FTD patients possessing elevated FLNC levels, identified multiple altered protein factors involved in accelerated aging, neurodegeneration and synaptogenesis.Our findings further support the involvement of aberrant FLNC expression levels in FTD pathogenesis. Identification of increased FLNC levels in aged Grn mice and impaired pathways related to aging and neurodegeneration, implies a potential role for FLNC in mediating or accelerating the aging process.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-015-0246-7) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Investigating the role of filamin C in Belgian patients with frontotemporal dementia linked to GRN deficiency in FTLD-TDP brains

Janssens

Philtjens

Kleinberger

et al. 2015

acta neuropathol commun

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“…; Beesley et al . ). These parasagittal bands have been described for numerous molecules (Ozol et al .…”

Section: Expression and Localization Of The Neuroplastinsmentioning

confidence: 97%

“…Transient global ischaemia also results in a large increase in the level of PSD‐associated Np65 (Beesley et al . ). A dynamic model for Np65 translocation into the PSD is supported by recent data which suggest that Np65 is a loosely bound rather than an integral PSD protein.…”

Section: Physiological Functions Of the Neuroplastinsmentioning

confidence: 97%

“…A significant role for Np65 in recovery from ischaemic insult is suggested by the threefold increase in Np65 in forebrain PSDs following transient ischaemia (Beesley et al . ). It is plausible that the increased Np65 level in PSDs is at least in part related to its function as an accessory protein and chaperone for MCT2, and possibly MCT1.…”

Section: A Role For Neuroplastin In Pathophysiology and Human Diseasementioning

confidence: 97%

“…This pattern of localization suggests that Np55 also plays important functional roles at the synapse. Strikingly, Np55 is expressed in parasagittal (zebrin) stripes (Marzban et al 2003;Beesley et al 2013). These parasagittal bands have been described for numerous molecules (Ozol et al 1999;Armstrong and Hawkes 2000) and most thoroughly investigated for Zebrin II/aldolase C (Brochu et al 1990;Ahn et al 1994).…”

Section: Expression and Localization Of The Neuroplastinsmentioning

confidence: 97%

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The Neuroplastin adhesion molecules: key regulators of neuronal plasticity and synaptic function

Beesley

Herrera-Molina

Smalla

et al. 2014

Journal of Neurochemistry

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The Neuroplastins Np65 and Np55 are neuronal and synapseenriched immunoglobulin superfamily molecules that play important roles in a number of key neuronal and synaptic functions including, for Np65, cell adhesion. In this review we focus on the physiological roles of the Neuroplastins in promoting neurite outgrowth, regulating the structure and function of both inhibitory and excitatory synapses in brain, and in neuronal and synaptic plasticity. We discuss the underlying molecular and cellular mechanisms by which the Neuroplastins exert their physiological effects and how these are dependent upon the structural features of Np65 and Np55, which enable them to bind to a diverse range of protein partners. In turn this enables the Neuroplastins to interact with a number of key neuronal signalling cascades. These include: binding to and activation of the fibroblast growth factor receptor; Np65 trans-homophilic binding leading to activation of p38 MAPK and internalization of glutamate (GluR1) receptor subunits; acting as accessory proteins for monocarboxylate transporters, thus affecting neuronal energy supply, and binding to GABA A a1, 2 and 5 subunits, thus regulating the composition and localization of GABA A receptors. An emerging theme is the role of the Neuroplastins in regulating the trafficking and subcellular localization of specific binding partners. We also discuss the involvement of Neuroplastins in a number of pathophysiological conditions, including ischaemia, schizophrenia and breast cancer and the role of a single nucleotide polymorphism in the human Neuroplastin (NPTN) gene locus in impairment of cortical development and cognitive functions.

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Protein Moonlighting and Human Health and Idiopathic Human Disease

2016

Protein Moonlighting in Biology and Medicine

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The Neuroplastins: Multifunctional Neuronal Adhesion Molecules—Involvement in Behaviour and Disease

Cited by 11 publications

References 108 publications

Investigating the role of filamin C in Belgian patients with frontotemporal dementia linked to GRN deficiency in FTLD-TDP brains

Investigating the role of filamin C in Belgian patients with frontotemporal dementia linked to GRN deficiency in FTLD-TDP brains

The Neuroplastin adhesion molecules: key regulators of neuronal plasticity and synaptic function

Protein Moonlighting and Human Health and Idiopathic Human Disease

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