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The lysosomal protein, LAMTOR1/p18, regulates learning and memory by controlling mTOR signaling pathways; alterations in this regulation contribute to the pathogenesis of Angelman syndrome

One of the Bi Lab projects over the last few years has focused on the mTOR (mechanistic/mammalian target of rapamycin) signaling pathway. mTOR consists of two complexes, mTORC1 and mTORC2, and integrates signals from nutrients, energy levels, growth factors, and stress status. We have recently found that mTORC1 activity is increased while mTORC2 activity is decreased in a mouse model of Angelman syndrome (AS), a disease caused by maternal UBE3A deficiency. The imbalance in mTORC1 and mTORC2 activity is causally related to learning and memory impairment and motor dysfunction in AS mice. Furthermore, we have found that increased mTORC1 activity is due to increased levels of LAMTOR1 (a.k.a. p18) in AS mice due to the lack of Ube3a-mediated degradation. Since abnormal mTOR signaling has been reported in other neurological disorders, including Alzheimer’s disease and autism spectrum disorders, our findings may have broad implications for the understanding of numerous neurological disorders.

Potential roles of p18-mTORC1 signaling in synaptic plasticity and learning and memory in wild-type mice (WT) and Angelman syndrome (AS) model mice.

Activation of mTORC1-dependent local protein synthesis increases levels of the immediate-early gene product, Arc (activity-regulated cytoskeleton-associated protein) in AS mice; Arc induces AMPAR endocytosis, which dampens synaptic plasticity and learning efficiency. Reduced mTORC2 activity also hinders synaptic plasticity and memory consolidation.

Regulation of potassium channels by UBE3A

Small conductance calcium-activated potassium channels (SK1-3) are widely distributed throughout the brain and other organs. SK2 channels play important roles in learning and memory and in abnormal brain functions, such as epilepsy and schizophrenia. We have recently shown that synaptic SK2 levels are regulated by UBE3A-mediated degradation, and that lack of this regulation resulting from UBE3A deletion contributes to learning impairment in Angelman syndrome mice. Currently, we are investigating whether protein kinase A-mediated regulation of SK2 channels influences their regulation by UBE3A. Since SK2 channels are widely expressed in mammalian brain, these findings have significant implications for a vast array of neurologic/neuropsychiatric disorders.

Regulation of SK2 channels by UBE3A and PKA facilitates the endocytosis of the channels. Lack of UBE3A-mediated regulation increases synaptic expression of SK2 channels, which impairs synaptic plasticity and neuronal rhythmic activity.

Lysosomal dysfunction in brain aging

We previously reported that lysosomal dysfunction started earlier than previously thought during aging in mammals and was already apparent in middle age. Recent studies have shown that lysosomes have much broad roles than just being a 鈥渃ellular digestion organelle鈥�; these functions include regulation of protein synthesis and degradation, lipid and glucose metabolism, and gene transcription, at the cellular level; lysosomes also play a significant role in learning and memory, immune function, and cancer development and aging process, etc., at the system level. We are currently developing in vitro and in vivo assays to further investigate the roles of lysosomes in age-related neurodegenerative diseases.

Selected Publications (from 2010)

2019

Heysieattalab S, Lee KH, Liu Y, Wang Y, Foy MR, Bi X, Baudry M (2019) Impaired cerebellar plasticity and eye-blink conditioning in calpain-1 knock-out mice. Neurobiol Learn Mem. 2019 Feb 5. pii: S1074-7427(19)30015-2. doi: 10.1016/j.nlm.2019.02.005. [Epub ahead of print] PMID: 30735788

 

Liu Y., Johe K., Sun J., Hao X., Wang Y., Bi X, Baudry M. (2019) Enhancement of synaptic plasticity and reversal of impairments in motor and cognitive functions in a mouse model of Angelman Syndrome by a small neurogenic molecule, NSI-189. Neuropharmacology. 2019 Jan;144:337-344. doi: 10.1016/j.neuropharm.2018.10.038. Epub 2018 Nov 5.PMID: 3002 0076 (2018) PMID: 30408487

 

2018

Sun J, Liu Y, Jia Y, Hao X, Lin WJ, Tran J, Lynch G, Baudry M, Bi X (2018). UBE3A-mediated p18/LAMTOR1 ubiquitination and degradation regulate mTORC1 activity and synaptic plasticity. Elife. 2018 Jul 18;7. pii: e37993. doi: 10.7554/eLife.37993. [Epub ahead of print] PMID: 30020076

 

Wang, Y., Bi, X., and Baudry M (2018) Calpain-2 as a therapeutic target for acute neuronal injury. Expert Opin Ther Targets. 2018 Jan;22(1):19-29. doi: 10.1080/14728222.2018.1409723. Epub 2017 Nov 28. Review. PMID: 29168923 PMID: 29168923

 

2017

Wang, Y., Hall R.A., Lee, M., Kamgar-Parsi, A., Bi, X., and Baudry M (2017) The tyrosine phosphatase PTPN13/FAP-1 links calpain-2, TBI and tau tyrosine phosphorylation. Sci Rep. 2017 Sep 18;7(1):11771. doi: 10.1038/s41598-017-12236-3. PMID: 28924170

 

Wang, Y., Liu Y., Lopez D., Lee M., Dayal S., Hurtado A., Bi, X., and Baudry M (2017) Protection against TBI-induced neuronal death with post-treatment with a selective calpain-2 inhibitor in mice. J Neurotrauma. 2017 Jun 8. doi: 10.1089/neu.2017.5024. [Epub ahead of print] PMID: 28594313

 

Zhu G., Briz V., Seinfeld J., Liu Y., Bi X., Baudry M. (2017) Calpain-1 deletion impairs mGluR-dependent LTD and fear memory extinction. Sci. Rep 2017 Feb 16;7:42788. doi: 10.1038/srep42788. PMID: 28202907

 

Sun J, Baudry M, Bi X. (2017) Novel neurobiological roles of UBE3A. Oncotarget. 2017 Feb 5. doi: 10.18632/oncotarget.15105. [Epub ahead of print] PMID: 28179584

 

 

2016

Seinfeld J, Baudry N, Xu X., Bi X., and Baudry M (2016) Differential activation of calpain-1 and calpain-2 following kainate-induced seizure activity in rats and mice. eNeuro 2016; 10.1523/ENEURO.0088-15.2016 PMID: 27622212

 

Liu Y., Sun J., Wang Y., Lopez D., Tran J., Bi X, Baudry M. (2016) Deleting both PHLPP1 and CANP1 rescues impairments in long-term potentiation and learning in both single knockout mice. Learn Mem. 2016 Jul 15;23(8):399-404. doi: 10.1101/lm.042721.116. Print 2016 Aug. PMID: 27421891

 

Wang, Y., Lopez D., Davey P.G., Cameron J., Nguyen K., Tran J., Marquez E., Liu Y., Bi, X., and Baudry M (2016) Calpain-1 and calpain-2 play opposite roles in retinal ganglion cell degeneration induced by retinal ischemia/reperfusion injury. Neurobiol Dis. 2016 Sep;93:121-8. doi: 10.1016/j.nbd.2016.05.007. Epub 2016 May 13. PMID: 27185592

 

Wang Y, Hersheson J, Lopez D, Hammer M, Liu Y, Lee KH, Pinto V, Seinfeld J, Wiethoff S, Sun J, Amouri R, Hentati F, Baudry N, Tran J, Singleton AB, Coutelier M, Brice A, Stevanin G, Durr A, Bi X, Houlden H, Baudry M. (2016) Defects in the CAPN1 gene result in alterations in cerebellar development and in cerebellar ataxia in mice and humans. Cell Rep. 2016 Jun 28;16(1):79-91. doi: 10.1016/j.celrep.2016.05.044. Epub 2016 Jun 16. PMID: 27320912.

 

Sun J., Liu Y., Tran J., O鈥橬eal P., Baudry M., and Bi X. (2016) mTORC1-S6K1 inhibition or mTORC2 activation improves hippocampal synaptic plasticity and learning in Angelman syndrome mice. Cell Mol Life Sci. 2016 Nov;73(22):4303-4314. PMID: 27173058

 

Liu Y, Wang Y., Zhu G, Sun J., Bi X, Baudry M. (2016) A calpain-2 selective inhibitor enhances learning & memory by prolonging ERK activation. Neuropharm. Feb 18;105:471-477. doi: 10.1016/j.neuropharm.2016.02.022. [Epub ahead of print] PMID: 26907807

 

Baudry M., and Bi X. (2016) Calpain-1 and calpain-2: The yin and yang of synaptic plasticity and neurodegeneration. Trend Neurosci. 39(4):235-45. doi: 10.1016/j.tins.2016.01.007. Epub 2016 PMID: 26874794

 

Bi, X. Sun, J, Ji, A.X. Baudry, M (2016) Potential therapeutic approaches for Angelman syndrome. Expert Opin Ther Targets. 2016 2016;20(5):601-13. doi: 10.1517/14728222.2016.1115837. PMID: 26558806

 

2015

Briz V, Liu Y, Zhu G, Bi X, Baudry M. (2015) A novel form of synaptic plasticity in field CA3 of hippocampus requires GPER1 activation and BDNF release. J Cell Biol 2015 Sep 28;210(7):1225-37. doi: 10.1083/jcb.201504092. Epub 2015 Sep 21. PMID: 26391661

 

Sun J, Liu Y, Zhu G., Standley S., Ji A., Tunuguntla R., Wang Y., Claus C., Lou Y., Baudry M., Bi X. (2015) UBE3A regulates synaptic plasticity and learning and memory by controlling SK2 channel endocytosis. Cell Rep. 2015 Jul 21;12(3):449-61. doi: 10.1016/j.celrep.2015.06.023. Epub 2015 Jul 9. PMID: 26166566

Bi, X. Sun, J, and Baudry, M (2015) Yin-and-Yang of mTORC1/C2 in Angelman syndrome. Oncotarget, Vol. 6, No. 16. 13844-13845. Editorial. PMID: 26116835

 

Liao G., Wang Z., Lee E., Moreno S., Abuelnasr O., Baudry M., Bi X (2015) Enhanced expression of matrix metalloproteinase-12 contributes to Npc1 deficiency-induced axonal degeneration. Exp Neurol 269:67-74. PMID: 25864931

 

Sun J, Liu Y, Moreno S., Baudry M, Bi X (2015) Imbalanced mTORC1 and mTORC2 activity in cerebellum of Angelman syndrome mice impairs motor function. J Neurosci 35(11): 4706-4718. PMID: 25788687

 

Briz V, Zhu G, Wang Y, Liu Y, Avetisyam M, Bi X, Baudry M. (2015) Activity-dependent rapid local RhoA synthesis is required for hippocampal synaptic plasticity. J Neurosci ;35(5):2269-2282. PMID: 25653381

 

Zhu G, Liu Y, Wang Y, Bi X, Baudry M. (2015) Different Patterns of Electrical Activity Lead to Long-term Potentiation by Activating Different Intracellular Pathways. J Neurosci ;35(2):621-33. PMID: 25589756

 

Baudry M, Zhu G, Liu Y, Wang Y, Briz V, Bi X. (2015) Multiple cellular cascades participate in long-term potentiation and in hippocampus-dependent learning. Brain Res. 2015 Sep 24;1621:73-81. doi: 10.1016/j.brainres.2014.11.033. Epub 2014 Dec 4. PMID: 25482663

 

2014

Wang, Y., Zhu, G., Briz, V., Hsu, Y.-T., Bi, X., and Baudry M, (2014) A molecular brake controls the magnitude of long-term potentiation. Nature Commun 2014;5:3051. doi: 10.1038/ncomms4051. PMID: 24394804

 

2013

Wang, Y., Briz V., Chishti A., Bi X., Baudry M. (2013) Distinct roles for 渭-calpain and m-calpain in synaptic NMDAR-mediated neuroprotection and extrasynaptic NMDAR-mediated neurodegeneration. J Neurosci. 2013 Nov 27;33(48):18880-92. doi: 10.1523/JNEUROSCI.3293-13.2013. PMID: 24285894

 

Baudry, M., Bi, X. (2013) Learning and memory: An emergent property of cell motility. Neurobiol Learn Mem. 2013 May 21;104C:64-72. PMID: 23707799

 

Briz, V., Hsu, Y.-T., Li, Y., Lee, E., Bi, X., and Baudry, M (2013) Calpain-2-mediated PTEN degradation contributes to BDNF-induced stimulation of dendritic protein synthesis. J. Neurosci. 2013 Mar 6;33(10):4317-28. PMID: 23467348

 

Baudry, M., Chou, M.M., and Bi, X. (2013) Targeting calpain in synaptic plasticity. Expert Opin Ther Targets. 2013 May;17(5):579-92. PMID: 23379852

 

Baudry, M., Bi, X., and Aguirr, C. (2012) Progesterone-estrogen interactions in synaptic plasticity and neuroprotection. Neuroscience. 2013 Jun 3;239:280-94. 2012 Nov 7. PMID: 23142339

 

2012

Allyson, J., Bi, X., Baudry, M., and Massicotte G. (2012) Maintenance of synaptic stability requires calcium-independent phospholipase A2 activity. Neural Plasticity. 2012:569149. doi: 10.1155/2012/569149. Epub 2012 May 20. PMID: 22685677

 

Baudry, M., Kramar, E., Xu, X., Zadran, H., Moreno, S., Lynch, G., Gall C., and Bi, X. (2012) Ampakines promote spine actin polymerization, long-term potentiation, and learning in a mouse model of Angelman Syndrome. Neurobiol. Dis. 47(2):210-5. Epub 2012 Apr 16. PMID: 22525571

 

Clausen A., Xu X., Bi X., and Baudry M. (2012) Effects of the superoxide dismutase/catalase mimetic EUK-207 in a mouse model of Alzheimer鈥檚 disease: Protection against and interruption of progression of amyloid and tau pathology and cognitive decline. J Alzheimers Dis. 30(1):183-208. PMID: 22406441

 

2011

Hsu Y.-T., Liao G., Bi X., Oka, T., Tamura, S., and Baudry, M. (2011) The PDE10A inhibitor, papaverine, differentially activates ERK in male and female rat striatal slices. Neuropharmacology. 2011 Dec;61(8):1275-81. Epub 2011 Jul 28. PMID: 21816164

 

Yu L., Rostamiani K., Hsu Y.-T., Wang Y., Bi X., and Baudry M. (2011) Calpain-mediated regulation of stargazin in adult rat brain. Neuroscience 2011 Mar 31;178:13-20. Epub 2011 Jan 20. PMID: 21256931

 

Baudry M., Bi X., Gall C.M., and Lynch G. (2011) The Biochemistry of Memory: The Twenty-Six Year Journey of a ‘New and Specific Hypothesis’ Neurobiol Learn Mem. 2011 Feb;95(2):125-33. Epub 2010 Dec 4. PMID: 21134478

 

2010

Zadran S., Bi X. and Baudry, M. (2010) Regulation of calpain-2 in neurons: Implications for synaptic plasticity. Mol. Neurobiol. 2010 Oct;42(2):143-150. Epub 2010 Oct 6. PMID: 20924799

 

Qin, Q., Liao, G., Baudry, M., and Bi X. (2010) Role of calpain-mediated p53 truncation in semaphorin 3A-induced axonal growth regulation. Proc. Nat. Acad. Sci. USA 107(31):13883-7. Epub 2010 Jul 19. PMID: 20643936

 

Qin Q., Liao, G., Baudry M., and Bi X. (2010) Cholesterol perturbation in mice results in p53 degradation and axonal pathology through p38 MAPK and Mdm2 activation. PLoS ONE 5(4): e9999. doi:10.1371/journal.pone.0009999 PMID: 20386595

 

Zadran S., Jourdi H., Rostamiani K., Qin Q., Bi X. and Baudry, M. (2010) BDNF- and EGF-mediated neuronal calpain activation through MAPK-dependent phosphorylation. J. Neurosci, 2010 30: 1086-1095 PMID: 20089917

 

Liao, G., Wen, Z., Irizarry, K., Huang, Y., Mitsouras, K., Darmani, M., Leon, T., Shi, L. and Bi, X. (2010). Abnormal gene expression in cerebellum of Npc1-/- mice during postnatal development. Brain Res. 1325:128-140 PMID: 20153740

 

Bi X, Liao G. (2010) Cholesterol in Niemann-Pick Type C disease. Subcell Biochem. 2010;51:319-35. doi: 10.1007/978-90-481-8622-8_11. Review. PMID: 20213549

 

 

 

	Jiandong Sun, PhD Senior Postdoctoral Researcher sunj@westernu.edu
	Yan Liu, PhD Postdoctoral Researcher yliu@westernu.edu
	Xiaoning Hao, MS Research Assistant xhao@westernu.edu
	Wei-Ju Lin MS student in Biomedical Sciences wjlin@westernu.edu