Reduced expression of BTBD10, an Akt activator, leads to motor neuron death

Abstract

BTBD10, an Akt interactor, activates Akt by decreasing the protein phosphatase 2A-mediated dephosphorylation and inactivation of Akt. Overexpression of BTBD10 suppresses motor neuron death that is induced by a familial amyotrophic lateral sclerosis (ALS)-linked superoxide dismutase 1 (SOD1) mutant, G93A-SOD1 in vitro. In this study, we further investigated the BTBD10-mediated suppression of motor neuron death. We found that the small interfering RNA-mediated inhibition of BTBD10 expression led to the death of cultured motor neurons. In Caenorhabditis elegans (C. elegans), disruption of the btbd-10 gene caused not only loss of neurons, including both motor and touch-receptor neurons, but also a locomotion defect. In addition, we found that the expression of BTBD10 was generally decreased in the motor neurons from patients of sporadic ALS and transgenic mice overexpressing G93A-SOD1 (G93A-SOD1-transgenic mice). Collectively, these results suggest that the reduced expression of BTBD10 leads to motor neuron death both in vitro and in vivo. A gain-of-toxic-function of an intracellular molecule or a loss of normal function of an essential intracellular molecule, including an intracellular prosurvival signal, contributes to cell death. The Akt family of proteins (Akt1, 2 and 3 in mammalian cells) provides a major intracellular prosurvival signal by phosphorylating many target proteins. 1 The major upstream activator of Akt is the phosphatidylinositol 3-kinase (PI3K)-mediated signal that activates Akt by phosphorylation. Akt's activity is also regulated by protein phosphatase-mediated dephosphorylation. 2 In our previous study, we showed that BTBD10 activates Akt by inhibiting protein phosphatase 2A (PP2A)-mediated Akt dephosphorylation. 3 Recent advances in genetics and neuroscience have suggested that both gains of toxic and/or losses of normal function of intracellular molecules contribute to the pathogenesis of neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS) is a representative motor neuron-specific neurodegenerative disease. 4 Approximately 10% of ALS cases are genetically inherited. 4,5 Dominant mutations in the superoxide dismutase 1 (SOD1) gene (the first identified familial ALS (FALS)-linked gene) account for approximately 20% of FALS cases. The gain-of-toxic-function of SOD1, caused by a FALS-linked mutation, is thought to be closely linked to the ALS pathogenesis. The second identified FALS-linked gene, a FALS-linked mutation of which results in an autosomal-recessive phenotype, encodes a protein named alsin. 6,7 Loss of alsin function, caused by a FALSlinked mutation, leads to the abnormal endolysosomal trafficking and contributes to motor neuron death. 8 We have independently shown that wild-type alsin suppresses mutant SOD1-induced neuronal cell death by activating a prosurvival pathway involving Rac1, PI3K and Akt3, and that FALS-linked mutations in the gene abolish the alsin function. 9,10 To further characterize the Akt-mediated prosurvival pathways that are linked to the ALS pathogenesi...

Programmed Cell Death DuringCaenorhabditis elegansDevelopment

“…This occurs in animals lacking the aminophospholipid translocase transbilayer amphipath transporter 1 (TAT-1) that maintains PS asymmetry in plasma membrane (Darland-Ransom et al 2008). These observations are confirmed by other studies in C. elegans Nawa et al 2012) and by a mammalian study in which inactivation of CDC50A, a cofactor for the human TAT-1 homolog ATP11C, causes ectopic PS exposure in living cells and their phagocytosis by macrophages (Segawa et al 2014). The engulfment of living cells by phagocytes in the tat-1 mutants is blocked by lf mutations in PS receptor family 1 (psr-1) and ced-1, two phagocyte receptors that recognize surface-exposed PS and act in two major phagocytosis pathways (Zhou et al 2001b;Wang et al 2003;DarlandRansom et al 2008;Wang et al 2010;Li et al 2015;Yang et al 2015), suggesting that externalized PS can serve as an eat me signal for both engulfment pathways.…”

BAFF Controls Neural Cell Survival through BAFF Receptor

“…3B ), suggesting that impaired Akt activation may contribute to accelerated apoptosis of Baffr m/m neurons. Several previous reports have shown the contribution of apoptosis [25], [26] and a protective role of Akt [7], [27], [28], [29], [30] in the motor neuron death in mSOD1 mice. Therefore, it is likely that BAFF-R signal plays a neuroprotective role in neurons of mSOD1 mice by activating Akt and suppressing apoptosis.…”

KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders

“…with Alzheimer's risk (GWAS) 110 Degrades RhoA 33,76 Regulates apoptosis 120 Inhibits NF-κB and AP-1 118 Aa a tumor suppressor in nonsmall cell lung cancer 121 Poor prognosis if overexpressed in breast cancer 122 Overexpressed in osteosarcoma 123 16,96 ) Inhibits mTORC1 activity 14 Inhibits Hh pathway by degrading HDAC 12 Deletion/ reduced expression in medulloblastoma 94 Loss of heterozygosity in prostate adenocarcinoma 129 Reduced expression in hepatocellular carcinoma 130 (Continues) Inhibits transcription factor AP-2α 9 and Wnt signaling by degrading β-catenin 131 I27N mutation caused kidney dysfunction in mice 132 Missense mutations associated with scalp-ear-nipple syndrome 133 Other Regulates GABA B2 signaling 17,135,136 ND Other KCNRG ND Kv channel 139,140 Suppresses K + channel activity 139 Deleted in B-cell chronic lymphocytic leukemia, [140][141][142] prostate cancer 140 and multiple myeloma 142 Other KCTD18 ND ND ND Duplication of 2q33 in one patient with epilepsy, devel. delay, autistic behavior 143 Haplotype associated with restless legs syndrome 144 G KCTD20 ND ND Activates Akt 145,146 Gen var associated with insulin resistance (GWAS) 147 BTBD10 ND Akt1-3 148 Inhibits apoptosis, activates Akt 149,150 Sporadic amyotrophic lateral sclerosis 151…”