TDP-43 regulates cholesterol biosynthesis by inhibiting sterol regulatory element-binding protein 2

Dyslipidemia is considered an essential component of the pathological process of amyotrophic lateral sclerosis (ALS), a fatal motor neuron disease. Although TAR DNA Binding Protein 43 kDa (TDP-43) links both familial and sporadic forms of ALS and cytoplasmic aggregates are a hallmark of most cases of ALS, the molecular mechanism and the in vivo relation of ALS dyslipidemia with TDP-43 have been unclear. To analyze the dyslipidemia-related gene expression by TDP-43, we performed expression microarray and RNA deep sequencing (RNA-Seq) using cell lines expressing high levels of TDP-43 and identified 434 significantly altered genes including sterol regulatory element-binding protein 2 (SREBP2), a master regulator of cholesterol homeostasis and its downstream genes. Elevated TDP-43 impaired SREBP2 transcriptional activity, leading to inhibition of cholesterol biosynthesis. The amount of cholesterol was significantly decreased in the spinal cords of TDP-43-overexpressed ALS model mice and in the cerebrospinal fluids of ALS patients. These results suggested that TDP-43 could play an essential role in cholesterol biosynthesis in relation to ALS dyslipidemia

MiR-33a is a therapeutic target in SPG4-related hereditary spastic paraplegia human neurons

Recent reports, including ours, have indicated that microRNA (miR)-33 located within the intron of sterol regulatory element binding protein (SREBP) 2 controls cholesterol homeostasis and can be a potential therapeutic target for the treatment of atherosclerosis. Here, we show that SPAST, which encodes a microtubule-severing protein called SPASTIN, was a novel target gene of miR-33 in human. Actually, the miR-33 binding site in the SPAST 3′-UTR is conserved not in mice but in mid to large mammals, and it is impossible to clarify the role of miR-33 on SPAST in mice. We demonstrated that inhibition of miR-33a, a major form of miR-33 in human neurons, via locked nucleic acid (LNA)-anti-miR ameliorated the pathological phenotype in hereditary spastic paraplegia (HSP)-SPG4 patient induced pluripotent stem cell (iPSC)-derived cortical neurons. Thus, miR-33a can be a potential therapeutic target for the treatment of HSP-SPG4

The Reaction Mechanism of Claisen Rearrangement Obtained by Transition State Spectroscopy and Single Direct-Dynamics Trajectory

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A CASE OF AN ISOLATED ADRENOCORTICOTROPIN (ACTH) DEFICIENCY : RESOLVED AND DELIVERED A CHILD AFTER 8 YEARS OF TREATMENT

We describe a 19-year-old Japanese woman with isolated ACTH deficiency who improved and delivered a child after 8 years hydrocortisone replacement therapy. Menarche was at the age of 13 y, and menstruation continued regularly. At the age of 16 y general fatigue and amenorrhea developed, and she was referred to our hospital. Her plasma ACTH and cortisol levels were low, and ACTH provocation tests revealed no response. Although the plasma ACTH and cortisol levels were low, dexamethasone suppressed them. Results of other pituitary function tests were normal. Autoantibodies against ACTH-producing cells were identified. She was diagnosed with isolated ACTH deficiency, and we initiated hydrocortisone replacement therapy. Her general 6ondition and anemia were improved, but the amenorrhea persisted. Seven years later, the hydrocortisone was tapered off and menstruation started again. At that time, the test for pituitary autoantibody was negative. One year after fisishl'ng hydrocortisone replacement therapy, she gave birth to a healthy child by natural delivery. This was an atypical case of isolated ACTH deficiency because the ACTH levels were not responsive to provocation tests but were suppressed by dexamethasone. We suggest that the deficiency of ACTH secretion was functional and transient due to the autoimmune mechanism

TDP-43 regulates cholesterol biosynthesis by inhibiting sterol regulatory element-binding protein 2

筋萎縮性側索硬化症（ALS）病因タンパク質TDP-43は コレステロール合成を制御する --ALSにおける脂質代謝異常と栄養療法の分子メカニズム探索--. 京都大学プレスリリース. 2022-05-16.ALS-related protein TDP-43 regulates cholesterol synthesis --Insight for molecular mechanisms of lipid metabolism and nutritional therapy in ALS--. 京都大学プレスリリース. 2022-05-20.Dyslipidemia is considered an essential component of the pathological process of amyotrophic lateral sclerosis (ALS), a fatal motor neuron disease. Although TAR DNA Binding Protein 43 kDa (TDP-43) links both familial and sporadic forms of ALS and cytoplasmic aggregates are a hallmark of most cases of ALS, the molecular mechanism and the in vivo relation of ALS dyslipidemia with TDP-43 have been unclear. To analyze the dyslipidemia-related gene expression by TDP-43, we performed expression microarray and RNA deep sequencing (RNA-Seq) using cell lines expressing high levels of TDP-43 and identified 434 significantly altered genes including sterol regulatory element-binding protein 2 (SREBP2), a master regulator of cholesterol homeostasis and its downstream genes. Elevated TDP-43 impaired SREBP2 transcriptional activity, leading to inhibition of cholesterol biosynthesis. The amount of cholesterol was significantly decreased in the spinal cords of TDP-43-overexpressed ALS model mice and in the cerebrospinal fluids of ALS patients. These results suggested that TDP-43 could play an essential role in cholesterol biosynthesis in relation to ALS dyslipidemia