精神疾患におけるバイオマーカー研究—毛根細胞を用いた例

Utility of Scalp Hair Follicles as a Novel Source of Biomarker Genes for Psychiatric Illnesses

抄録

　精神疾患のバイオマーカー探索の新たな生体試料として，発生学的に脳の細胞と同じ外胚葉由来である頭皮の毛根細胞に着目し，解析を行った。その結果，脳だけで発現していると考えられていた遺伝子の多くが毛根細胞でも発現していること，統合失調症患者の毛根細胞では脂肪酸結合タンパク質(FABP)の1つをコードするFABP4遺伝子の発現量が約40％低下していること，FABP4遺伝子の発現量低下は，年齢や性別，服薬，罹病期間などに影響されないことが判明した。また，成人の自閉症スペクトラム症の毛根細胞では，神経系の細胞同士の結合に関与するCNTNAP2遺伝子の発現が低下していることを見出した。

　Identifying the beneficial surrogate markers in psychiatric disorders is crucial but challenging. Given that the scalp hair follicles are easily accessible and, like the brain, are derived from the ectoderm, expressions of messenger RNA (mRNA) and micro RNA (miRNA) in the organ were examined between two sets of between schizophrenia and control with schizophrenia. We selected the genes for GABA (γ-aminobutyric acid)-ergic system components, myelin and fatty acids, as schizophrenia-relevant genes. We examined whether those genes are expressed in the hair follicles, and if so, whether the expression differs between cases and controls. Among the genes examined, mRNA levels of FABP4 (gene for fatty acid binding protein 4) were downregulated in subjects with schizophrenia in two independent sample sets. FABP4 mRNA levels were also analyzed in postmortem brains, induced pluripotent stem cells, and pluripotent stem cell-derived neurospheres to determine its role in the central nervous system. FABP4 was expressed from the neurosphere stage. Additionally, microarray-based miRNA analysis showed a trend of increased expression of hsa-miR-4449 (p＝0.0634) in the hair follicles in schizophrenia. hsa-miR-4449 expression was increased in BA (Brodmann Area) 46 in schizophrenia postmortem brains (p＝0.0007). Lastly, we tested the expression of nine putative autism candidate genes in the hair follicles and found decreased CNTNAP2 (gene for contactin associated protein-like 2) expression in the autism cohort. Collectively, our results suggest that the scalp hair follicles could be a beneficial genetic biomarker resource for neurologic diseases, and that further studies on FABP4 are merited in schizophrenia pathogenesis.