Multiple Functions of <em>Fukutin</em>, the Gene Responsible for Fukuyama Congenital Muscular Dystrophy, Especially in the Central Nervous System

Fukuyama congenital muscular dystrophy (FCMD), accompanying central nervous system (CNS) and ocular anomalies, is the second common muscular dystrophy in Japan, and the responsible gene is fukutin. The lesions are mainly caused by fragile basement membrane/cell membrane due to hypoglycosylation of α-dystroglycan (α-DG), and astrocytes play a crucial role for CNS malformation. On the other hand, since fukutin is expressed almost ubiquitously, diverse functions of fukutin, besides the glycosylation of α-DG, can be considered. As for the CNS, fukutin possibly upregulates cyclin D1 expression as a cofactor of activator protein-1 in astrocytoma. Moreover, fukutin may be involved in the phosphorylation of tau, one of the key proteins of dementia represented by Alzheimer’s disease, in glutamatergic neurons. A presynaptic function in GABAergic neurons is also suggested. Owing to the recent advances of molecular and biochemical techniques, new therapeutic strategies are under consideration, even for brain malformation, which begins to be formed during the first trimester in utero. Recovery of hypoglycosylation of α-DG supposed to be a main therapeutic target, but to know various functions and regulation systems of fukutin might be important for developing suitable therapies

Fukutin Protein Participates in Cell Proliferation by Enhancing Cyclin D1 Expression through Binding to the Transcription Factor Activator Protein-1: An In Vitro Study

The causative gene of Fukuyama congenital muscular dystrophy (fukutin) is involved in formation of the basement membrane through glycosylation of alpha-dystroglycan. However, there are other proposed functions that have not been fully understood. Using cultured astrocytes (1321N1), we found nuclear localization of fukutin and a positive relationship between fukutin expression and cell proliferation. Among potential proteins regulating cell proliferation, we focused on cyclin D1, by reverse-transcription polymerase chain reaction, Western blotting, immunocytochemistry, enzyme-linked immunosorbent assay (ELISA), and sandwich ELISA. Expression of cyclin D1 was significantly downregulated by fukutin knockdown and significantly upregulated by fukutin overexpression. Moreover, fukutin was proven to bind to the activator protein-1 (AP-1) binding site of cyclin D1 promoter, as well as the AP-1 component c-Jun. The c-Jun phosphorylation status was not significantly influenced by knockdown or overexpression of fukutin. The present results provide in vitro evidence for a novel function of fukutin, which participates in cell proliferation by enhancing cyclin D1 expression through forming a complex with AP-1. It is likely that fukutin is a potential cofactor of AP-1

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

Fukutin, a product of the causative gene of Fukuyama congenital muscular dystrophy (FCMD), is known to be responsible for basement membrane formation. Patients with FCMD exhibit not only muscular dystrophy but also central nervous system abnormalities, including polymicrogyria and neurofibrillary tangles (NFTs) in the cerebral cortex. The formation of NFTs cannot be explained by basement membrane disorganization. To determine the involvement of fukutin in the NFT formation, we performed molecular pathological investigations using autopsied human brains and cultured neurons of a cell line (SH‐SY5Y). In human brains, NFTs, identified with an antibody against phosphorylated tau (p‐tau), were observed in FCMD patients but not age‐matched control subjects and were localized in cortical neurons lacking somatic immunoreactivity for glutamic acid decarboxylase (GAD), a marker of inhibitory neurons. In FCMD brains, NFTs were mainly distributed in lesions of polymicrogyria. Immunofluorescence staining revealed the colocalization of immunoreactivities for p‐tau and phosphorylated glycogen synthase kinase‐3β (GSK‐3β), a potential tau kinase, in the somatic cytoplasm of SH‐SY5Y cells; both the immunoreactivities were increased by fukutin knockdown and reduced by fukutin overexpression. Western blot analysis using SH‐SY5Y cells revealed consistent results. Enzyme‐linked immunosorbent assay (ELISA) confirmed the binding affinity of fukutin to tau and GSK‐3β in SH‐SY5Y cells. In the human brains, the density of GAD‐immunoreactive neurons in the frontal cortex was significantly higher in the FCMD group than in the control group. GAD immunoreactivity on Western blots of SH‐SY5Y cells was significantly increased by fukutin knockdown. On immunofluorescence staining, immunoreactivities for fukutin and GAD were colocalized in the somatic cytoplasm of the human brains and SH‐SY5Y cells, whereas those for fukutin and synaptophysin were colocalized in the neuropil of the human brains and the cytoplasm of SH‐SY5Y cells. ELISA confirmed the binding affinity of fukutin to GAD and synaptophysin in SH‐SY5Y cells. The present results provide in vivo and in vitro evidence 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

mTOR Complexes as a Nutrient Sensor for Driving Cancer Progression

Recent advancement in the field of molecular cancer research has clearly revealed that abnormality of oncogenes or tumor suppressor genes causes tumor progression thorough the promotion of intracellular metabolism. Metabolic reprogramming is one of the strategies for cancer cells to ensure their survival by enabling cancer cells to obtain the macromolecular precursors and energy needed for the rapid growth. However, an orchestration of appropriate metabolic reactions for the cancer cell survival requires the precise mechanism to sense and harness the nutrient in the microenvironment. Mammalian/mechanistic target of rapamycin (mTOR) complexes are known downstream effectors of many cancer-causing mutations, which are thought to regulate cancer cell survival and growth. Recent studies demonstrate the intriguing role of mTOR to achieve the feat through metabolic reprogramming in cancer. Importantly, not only mTORC1, a well-known regulator of metabolism both in normal and cancer cell, but mTORC2, an essential partner of mTORC1 downstream of growth factor receptor signaling, controls cooperatively specific metabolism, which nominates them as an essential regulator of cancer metabolism as well as a promising candidate to garner and convey the nutrient information from the surrounding environment. In this article, we depict the recent findings on the role of mTOR complexes in cancer as a master regulator of cancer metabolism and a potential sensor of nutrients, especially focusing on glucose and amino acid sensing in cancer. Novel and detailed molecular mechanisms that amino acids activate mTOR complexes signaling have been identified. We would also like to mention the intricate crosstalk between glucose and amino acid metabolism that ensures the survival of cancer cells, but at the same time it could be exploitable for the novel intervention to target the metabolic vulnerabilities of cancer cells

Near-infrared characterization of ultra-diffuse galaxies in Abell 2744 by JWST/NIRISS imaging

We present a search and characterization of ultra-diffuse galaxies (UDGs) in the Frontier Fields cluster Abell~2744 at $z=0.308$. We use JWST/NIRISS F200W observations, acquired as part of the GLASS-JWST Early Release Science Program, aiming to characterize morphologies of cluster UDGs and their diffuse stellar components. A total number of 22 UDGs are identified by our selection criteria using morphological parameters, down to stellar mass of $\sim10^{7}M_{\odot}$. The selected UDGs are systematically larger in effective radius in F200W than in HST/ACS F814W images, which implies that some of them would not have been identified as UDGs when selected at rest-frame optical wavelengths. In fact, we find that about one third of the UDGs were not previously identified based on the F814W data. We observe a flat distribution of the UDGs in the stellar mass-size plane, similar to what is found for cluster quiescent galaxies at comparable mass. Our pilot study using the new JWST F200W filter showcases the efficiency of searching UDGs at cosmological distances, with 1/30 of the exposure time of the previous deep observing campaign with HST. Further studies with JWST focusing on spatially-resolved properties of individual sources will provide insight into their origin.Comment: Submitted to MNRAS, 10 pages, 9 figures, 2 table