Fukutin regulates tau phosphorylation and synaptic function: Novel properties of fukutin in neurons

Abstract

dence for novel properties of fukutin as follows: (i) there is an inverse relationship between fukutin expression and GSK-3β/tau phosphorylation in neurons; (ii) fukutin binds to GSK-3β and tau; (iii) tau phosphorylation occurs in non-GAD-immunoreactive neurons in FCMD brains; (iv) neuronal GAD expression is upregulated in the absence of fukutin; and (v) fukutin binds to GAD and synaptophysin in presynaptic vesicles of neurons.

Perspective Chapter: Multiple Functions of Fukutin, the Gene Responsible for Fukuyama Congenital Muscular Dystrophy, Especially in the Central Nervous System

“…In the cerebrum of our adult FCMD patient, immunoreaction against anti-GAD antibody is increased [38]. Several factors can be postulated for the explanation, e.g., compensation toward hyperactivities of glutamatergic neurons, reaction against abnormal postsynaptic or presynaptic functions, etc.…”

“…Using neuroblastoma cell lines, we have found that the phosphorylation of both tau and GSK-3β is augmented by suppression of fukutin and is reduced by overexpression of fukutin [38]. Moreover, fukutin, tau, and GSK-3β are suggested to form a complex (Figure 4) [38]. Fukutin is possibly involved in the phosphorylation of tau, mediated by GSK-3β, which appears to be independent from the glycosylation of α-DG.…”

“…On immunohistochemical examination of the cerebrum of FCMD cases, neurons containing p-tau-positive NFT do not express GAD. NFTs are likely to be formed in excitatory neurons (Figure 3) [38]. Abnormal architectures of neurons derived from the disruption of glia limitans may be one of the factors to give rise to NFTs, considering from the distribution of neurons containing NFT.…”

“…One of the representative proteins is glycogen synthase kinase-3 (GSK-3β) [42]. Using neuroblastoma cell lines, we have found that the phosphorylation of both tau and GSK-3β is augmented by suppression of fukutin and is reduced by overexpression of fukutin [38]. Moreover, fukutin, tau, and GSK-3β are suggested to form a complex (Figure 4) [38].…”

“…It is curious to know whether fukutin itself directly implicated in this phenomenon or not. A loss of fukutin appears to trigger the increase of GAD, because the increase is observed throughout the cerebral cortex, including the occipital robe showing almost normal histological appearance [38]. The dystrophin-dystroglycan complex (DGC) is existed in the postsynapse, and postsynaptic function of α-DG is well known [6,44].…”