Bakkar Laboratory

Choroid Plexus Alterations in Neurodegeneration 

We focus on the blood-CSF barrier and its involvement in neurodegeneration. We hypothesized that the blood-CSF barrier is disrupted at the level of the choroid plexus in amyotrophic lateral sclerosis (ALS) and use multiple tools to investigate structural and functional changes mediated by the disease. We have found alterations in the choroid plexus in post-mortem human ALS samples both at the level of RNA (by RNA-seq) and protein (immunohistochemistry) and are pursuing models to further investigate these changes and their effects on the function and permeability of this barrier. We have also expanded our investigation of blood-CSF barrier alterations to other neurodegenerative diseases including frontotemporal dementia (FTD), focusing on commonalities and differences between neurodegenerative diseases at the level of the choroid plexus. 

RNA Binding Protein in ALS 

Another project in the lab focuses on RNA binding protein alterations in ALS, and specifically on Caprin-1, an RNA granule member that resides in the neuronal pre-synaptic compartment. We have previously linked Caprin-1 to ALS using the literature mining computing abilities of IBM-Watson are further investigating these changes. Preliminary data indicates Caprin-1 is upregulated in frontal cortex of ALS cases associated with dementias (ALS-FTD) and we are further investigating the nature of these changes.  

Our research is funded by the following organizations: 

• ALS Association 
• Barrow Neurological Foundation 
• Arizona Biomedical Research Center (Link https://azdhs.gov/biomedical/) 

• Arizona Alzheimer’s Consortium (Link https://azalz.org/) 

1. Saul J, Hutchins E, Reiman R, Saul M, Ostrow LW, Harris BT, Van Keuren-Jensen K, Bowser R, Bakkar N. Global alterations to the choroid plexus blood-CSF barrier in amyotrophic lateral sclerosis. Acta Neuropathol Commun. 2020 Jun 26;8(1):92. doi: 10.1186/s40478-020-00968-9. 

2. Peterson JM, Wang DJ, Shettigar V, Roof SR, Canan BD, Bakkar N, Shintaku J, Gu JM, Little SC, Ratnam NM, Londhe P, Lu L, Gaw CE, Petrosino JM, Liyanarachchi S, Wang H, Janssen PML, Davis JP, Ziolo MT, Sharma SM, Guttridge DC. NF-κB inhibition rescues cardiac function by remodeling calcium genes in a Duchenne muscular dystrophy model. Nat Commun. 2018 Aug 24;9(1):3431. doi: 10.1038/s41467-018-05910-1. 

3. Bakkar N, Kovalik T, Lorenzini I, Spangler S, Lacoste A, Sponaugle K, Ferrante P, Argentinis E, Sattler R, Bowser R. Artificial intelligence in neurodegenerative disease research: use of IBM Watson to identify additional RNA-binding proteins altered in amyotrophic lateral sclerosis. Acta Neuropathol. 2018. Feb;135(2):227-247. doi: 10.1007/s00401-017-1785-8. 

4. Boehringer A, Garcia-Mansfield K, Singh G, Bakkar N, Pirrotte P, Bowser R. ALS Associated Mutations in Matrin 3 Alter Protein-Protein Interactions and Impede mRNA Nuclear Export. Sci Rep. 2017;7(1):14529. doi: 10.1038/s41598-017-14924-6. 

5. Li Y, Collins M, Geiser R, Bakkar N, Riascos D, Bowser R. RBM45 homo-oligomerization mediates association with ALS-linked proteins and stress granules. Sci Rep. 2015 Sep 22;5:14262. doi: 10.1038/srep14262. 

6. Bakkar N, Kousari A, Kovalik T, Li Y, Bowser R. RBM45 Modulates the Antioxidant Response in Amyotrophic Lateral Sclerosis through Interactions with KEAP1. Mol Cell Biol. Jul 2015;35(14):2385-2399. doi: 10.1128/MCB.00087-15. 

7. Bakkar N, Boehringer A, Bowser R. Use of biomarkers in ALS drug development and clinical trials. Brain Res. May 14 2015;1607:94-107. doi: 10.1016/j.brainres.2014.10.031. 

8. Balkhi MY, Iwenofu OH, Bakkar N, Ladner KJ, Chandler DS, Houghton PJ, London CA, Kraybill W, Perrotti D, Croce CM, Keller C, Guttridge DC. miR-29 acts as a decoy in sarcomas to protect the tumor suppressor A20 mRNA from degradation by HuR. Sci Signal. Jul 30 2013;6(286):ra63. doi: 10.1126/scisignal.2004177. 

9. Bakkar N, Ladner K, Canan BD, Liyanarachchi S, Bal NC, Pant M, Periasamy M, Li Q, Janssen PM, Guttridge DC. IKKalpha and alternative NF-kappaB regulate PGC-1beta to promote oxidative muscle metabolism. J Cell Biol. Feb 20 2012;196(4):497-511. doi: 10.1083/jcb.201108118. 

10. Peterson JM, Bakkar N, Guttridge DC. NF-kappaB signaling in skeletal muscle health and disease. Curr Top Dev Biol. 2011;96:85-119. doi: 10.1016/B978-0-12-385940-2.00004-8. 

11. Dahlman JM, Bakkar N, He W, Guttridge DC. NF-kappaB functions in stromal fibroblasts to regulate early postnatal muscle development. J Biol Chem. Feb 19 2010;285(8):5479-5487.  doi: 10.1074/jbc.M109.075606. 

12. Bakkar N, Guttridge DC. NF-kappaB signaling: a tale of two pathways in skeletal myogenesis. Physiol Rev. Apr 2010;90(2):495-511. doi: 10.1152/physrev.00040.2009. 

13. Dahlman JM, Wang J, Bakkar N, Guttridge DC. The RelA/p65 subunit of NF-kappaB specifically regulates cyclin D1 protein stability: implications for cell cycle withdrawal and skeletal myogenesis. J Cell Biochem. Jan 1 2009;106(1):42-51. doi: 10.1002/jcb.21976. 

14. Bakkar N, Wang J, Ladner KJ, Wang H, Dahlman JM, Carathers M, Acharyya S, Rudnicki MA, Hollenbach AD, Guttridge DC. IKK/NF-kappaB regulates skeletal myogenesis via a signaling switch to inhibit differentiation and promote mitochondrial biogenesis. J Cell Biol. Feb 25 2008;180(4):787-802. doi: 10.1083/jcb.200707179. 

15. Wang H, Hertlein E, Bakkar N, Sun H, Acharyya S, Wang J, Carathers M, Davuluri R, Guttridge DC. NF-kappaB regulation of YY1 inhibits skeletal myogenesis through transcriptional silencing of myofibrillar genes. Mol Cell Biol. 2007 Jun;27(12):4374-87. doi: 10.1128/MCB.02020-06.  

16.  Acharyya S, Villalta SA, Bakkar N, Bupha-Intr T, Janssen PM, Carathers M, Li ZW, Beg AA, Ghosh S, Sahenk Z, Weinstein M, Gardner KL, Rafael-Fortney JA, Karin M, Tidball JG, Baldwin AS, Guttridge DC. Interplay of IKK/NF-kappaB signaling in macrophages and myofibers promotes muscle degeneration in Duchenne muscular dystrophy. J Clin Invest. 2007 Apr;117(4):889-901. doi: 10.1172/JCI30556.  

17. Hertlein E, Wang J, Ladner KJ, Bakkar N, Guttridge DC. RelA/p65 regulation of IkappaBbeta. Mol Cell Biol. 2005 Jun;25(12):4956-68. doi: 10.1128/MCB.25.12.4956-4968.2005. 

18. Bakkar N, Wackerhage, H, Guttridge DC. Myostatin and NF‐κB Regulate Skeletal Myogenesis Through Distinct Signaling Pathways. Signal Transduction. 2005.Vol5 (4):202-10. doi.org/10.1002/sita.200400039 

19. Mikati MA, Holmes GL, Werner S, Bakkar N, Carmant L, Liu Z, Stafstrom CE. Effects of nimodipine on the behavioral sequalae of experimental status epilepticus in prepubescent rats. Epilepsy Behav. 2004 Apr;5(2):168-74. doi: 10.1016/j.yebeh.2003.12.002. 

20. Gali-Muhtasib H, Bakkar N. Modulating cell cycle: current applications and prospects for future drug development. Curr Cancer Drug Targets. 2002 Dec;2(4):309-36. doi: 10.2174/1568009023333809.