HookLaboratory Page

Research of the Hook laboratory has defined new protease mechanisms involved in neuronal cell death and severe memory loss. Cathepsin B has been validated in gene knockout studies to participate in memory deficits and amyloid pathology in a mouse model of AD. Small molecule inhibitors of cathepsin B are also effective for improving memory deficits and reducing A; new inhibitors are being developed for AD.

1. Kindy, M., Yu, J., Zhu, H., El-Amouri, S.S., Hook, V., and Hook, G.R. (2012) Deletion of the cathepsin B gene improves memory deficits in a transgenic Alzheimer’s disease mouse model expressing AbetaPP containing the wild-type beta-secretase site sequence. J. Alzheimer’s Disease 29, 827-840.
2. Hook, V., Yu, J., Hook, G., and Kindy, .S. (2014) N-Terminally truncated pGlu-Abeta is actively produced by cathepsin B. J. Alzheimer’s Disease 41, 129-149. PMCID: PMC4059604
3. Hook G, Hook V, Kindy M. The cysteine protease inhibitor, E64d, reduces brain amyloid-β and improves memory deficits in Alzheimer's disease animal models by inhibiting cathepsin B, but not BACE1, β- secretase activity. J Alzheimers Dis. 2011;26(2):387-408. PMCID: PMC4317342.
4. Podvin S, Jones A, Liu Q, Aulston B, Ransom LS, Ames J, Shen G, Lietz CB, Jiang Z, O'Donoghue AJ, Winston C, Ikezu T, Rissman R, Yuan S, Hook V. Dysregulation of exosome cargo by mutant tau expressed in human-Induced pluripotent stem cell (iPSC) neurons revealed by proteomics analyses. Mol Cell Proteomics. 2020 Apr 15. PMID: 32295833.
5. Yoon MC, Solania A, Jiang Z, Christy MP, Podvin S, Mosier C, Lietz CB, Ito G, Gerwick WH, Wolan DW, Hook G, O'Donoghue AJ, Hook V. Selective Neutral pH Inhibitor of Cathepsin B Designed Based on Cleavage Preferences at Cytosolic and Lysosomal pH Conditions. ACS Chem Biol. 2021 Sep 17;16(9):1628-1643. PMID: 34416110.
6. Boyarko B, Hook V. Human Tau Isoforms and Proteolysis for Production of Toxic Tau Fragments in Neurodegeneration. Front Neurosci. 2021 Oct 21;15:702788. PMCID: PMC8566764.

Advancements in defining pivotal mechanisms in TBI-directed pathways to brain dysfunction is necessary for finding an effective drug target for development of TBI therapeutics. Our seminal research identified cathepsin B, in gene knockout studies, to be involved as a key regulator of TBI-caused injuries. These findings support discovery of inhibitors of cathepsin B for development of drug to treat TBI.

1. Hook GR, Yu J, Sipes N, Pierschbacher MD, Hook V, and Kindy MS. (2014) Cathepsin B is an important new therapeutic target for treating traumatic brain injury. J. Neurotrauma 31, 515-529. PMCID: PMC3934599
2. Hook G, Jacobsen JS, Grabstein K, Kindy M, Hook V. Cathepsin B is a new drug target for traumatic brain injury therapeutics: evidence for E64d as a promising lead drug candidate. Front Neurol. 2015 Sep 2;6:178. PMCID: PMC4557097.
3. Boutté AM, Hook V, Thangavelu B, Sarkis GA, Abbatiello BN, Hook G, Jacobsen JS, Robertson CS, Gilsdorf J, Yang Z, Wang KKW, Shear DA. Penetrating traumatic brain injury triggers dysregulation of cathepsin B protein levels independent of cysteine protease activity in brain and cerebral spinal fluid. J Neurotrauma 2020 Apr 2. PMID: 31973644.
4. Hook V, Yoon M, Mosier C, Ito G, Podvin S, Head BP, Rissman R, O'Donoghue AJ, Hook G. Cathepsin B in neurodegeneration of Alzheimer's disease, traumatic brain injury, and related brain disorders. Biochim Biophys Acta Proteins Proteom. 2020 Apr 16:140428. PMID: 32305689.

The Hook laboratory has been a major contributor to the neuropeptide field for elucidating the protease pathways involved in converting pro-neuropeptides into active peptide neurotransmitters. The Hook laboratory define the cysteine protease pathway consisting of cathepsin L and human-specific cathepsin B, combined with the serine proteases PC1 and PC2, for peptide neurotransmitter biosynthesis.

1. Podvin S, Yaksh T, Hook V. The emerging role of spinal dynorphin in chronic pain: a therapeutic perspective. Annu Rev Pharmacol Toxicol. 2016;56:511-33. PMCID: PMC4902163.
2. Minokadeh A, Funkelstein L, Toneff T, Hwang SR, Beinfeld M, Reinheckel T, Peters C, Zadina J, Hook V. Cathepsin L participates in dynorphin production in brain cortex, illustrated by protease gene knockout and expression. Mol Cell Neurosci. 2010 Jan;43(1):98-107. PMID: 19837164.
3. Funkelstein, L., Lu, W.D., Koch, B., Mosier, C., Toneff, T., Taupenot, L., O’Connor, D.T., Reinheckel, T., Peters, C., Hook, V. (2012) Human cathepsin V protease participates in production of enkephalin and NPY neuropeptide neurotransmitters. J. Biol. Chem. 287, 15232-15241. PMCID: PMC3346103
4. Hook V, Lietz CB, Podvin S, Cajka T, Fiehn O. Diversity of Neuropeptide Cell-Cell Signaling Molecules Generated by Proteolytic Processing Revealed by Neuropeptidomics Mass Spectrometry. J Am Soc Mass Spectrom. 2018 May;29(5):807-816. PMID: 29667161.
5. Jiang Z, Lietz CB, Podvin S, Yoon MC, Toneff T, Hook V, O'Donoghue AJ. Differential Neuropeptidomes of Dense Core Secretory Vesicles (DCSV) Produced at Intravesicular and Extracellular pH Conditions by Proteolytic Processing. ACS Chem Neurosci. 2021 Jul 7;12(13):2385-2398. PMCID: PMC8267839.

Mass spectrometry-based neuropeptidomics, targeted metabolomics, and proteomics are investigated to gain undersanding of complex synaptic systems for neurotransmission. Global profiling of peptide and small molecule neurotransmitters, combined with synaptic proteome systems, allows elucidation of normal and disease mechanisms of synaptic neurotransmission.

1. Gupta, N., Bark, S.J., Lu, W.D., Taupenot, L., O’Connor, D.T., Pevzner, P., and Hook, V. (2010) Mass spectrometry-based neuropeptidomics of secretory vesicles from human adrenal medullary pheochromocytoma reveals novel peptide products of prohormone processing. J. Proteome Res. 9, 5065-5075. PMCID: PMC3000314
2. Wegrzyn, J.L., Bark, S.J., Funkelstein, L., Mosier, C.A., Yap, A., Kazemi-Esfarjani, P., La Spada, J.L., Sigurdson, C., O’Connor, D.T., and Hook, V. (2010) Proteomics of dense core secretory vesicles reveal distinct protein categories for secretion of neuroeffectors for cell-cell communication. J. Proteome Res. 9, 5002-5024. PMCID: PMC2996463
3. Hook V, Kind T, Podvin S, Palazoglu M, Tran C, Toneff T, Samra S, Lietz C, Fiehn O. Metabolomics analyses of 14 classical neurotransmitters by GC-TOF with LC-MS illustrates secretion of 9 cell-cell signaling molecules from sympathoadrenal chromaffin cells in the presence of lithium. ACS Chem Neurosci. 2019 Mar 20;10(3):1369-1379. PMID: 30698015.
4. Jiang Z, Lietz CB, Podvin S, Yoon MC, Toneff T, Hook V, O'Donoghue AJ. Differential Neuropeptidomes of Dense Core Secretory Vesicles (DCSV) Produced at Intravesicular and Extracellular pH Conditions by Proteolytic Processing. ACS Chem Neurosci. 2021 Jul 7;12(13):2385-2398. PMCID: PMC8267839.

Our human-focused research utilizes human-derived iPSC neurons from schizophrenia patients, human iPSC neurons and cell lines for neurotransmitter studies, , and human iPSC-derived exosomes involved in tau propagation.

1. Hook, V., Brennand, K., Kim, Y., Toneff, T., Funkelstein, L., Lee, KC, Ziegler, M., and Gage, FH. (2014). Human iPSC neurons display activity-dependent neurotransmitter secretion: aberrant catecholamine levels in schizophrenia neurons. Stem Cell Reports 3, 531-538. PMCID: PMC4223699
2. Bark, S.J., Wegrzyn, J., Taupenot, L., Ziegler, M., O’Connor, D., Ma, Q., Smoot, M., Ideker, T., and Hook, V. (2012) The protein architecture of human secretory vesicles reveals differential regulation of signaling molecule secretion by protein kinases. PloS ONE 7, e41134. PMCID: PMC3420874
3. Funkelstein, L., Lu, W.D., Koch, B., Mosier, C., Toneff, T., Taupenot, L., O’Connor, D.T., Reinheckel, T., Peters, C., Hook, V. (2012) Human cathepsin V protease participates in production of enkephalin and NPY neuropeptide neurotransmitters. J. Biol. Chem. 287, 15232-15241. PMCID: PMC3346103
4. Podvin S, Jones A, Liu Q, Aulston B, Ransom LS, Ames J, Shen G, Lietz CB, Jiang Z, O'Donoghue AJ, Winston C, Ikezu T, Rissman R, Yuan S, Hook V. Dysregulation of exosome cargo by mutant tau expressed in human-Induced pluripotent stem cell (iPSC) neurons revealed by proteomics analyses. Mol Cell Proteomics. 2020 Apr 15. PMID: 32295833.
5. Campeau A, Mills RH, Stevens T, Rossitto LA, Meehan M, Dorrestein P, Daly R, Nguyen TT, Gonzalez DJ, Jeste DV, Hook V. Multi-omics of human plasma reveals molecular features of dysregulated inflammation and accelerated aging in schizophrenia. Mol Psychiatry. 2021 Nov 5. PMID: 34741130.

Marine natural products from the sea are being explored as a rich source of bioactive molecules as protease inhibitors, in collaboration with the Scripps Institute of Oceanography at UC San Diego. These inhibitors are utilized for drug discovery in the nervous system.

1. Miller B, Friedman AJ, Choi H, Hogan J, McCammon JA, Hook V, Gerwick WH. The marine Cyanobacterial metabolite gallinamide A is a potent and selective inhibitor of human cathepsin L. J Nat Prod. 2014 Jan 24;77(1):92-9. PMCID: PMC3932306.
2. Boudreau PD, Miller BW, McCall LI, Almaliti J, Reher R, Hirata K, Le T, Siqueira-Neto JL, Hook V, Gerwick WH. Design of Gallinamide A Analogs as Potent Inhibitors of the Cysteine Proteases Human Cathepsin L and Trypanosoma cruzi Cruzain. J Med Chem. 2019 Oct 24;62(20):9026-9044. PMID: 31539239.
3. Ashhurst AS, Tang AH, Fajtová P, Yoon MC, Aggarwal A, Bedding MJ, Stoye A, Beretta L, Pwee D, Drelich A, Skinner D, Li L, Meek TD, McKerrow JH, Hook V, Tseng CT, Larance M, Turville S, Gerwick WH, O'Donoghue AJ, Payne RJ. Potent Anti-SARS-CoV-2 Activity by the Natural Product Gallinamide A and Analogues via Inhibition of Cathepsin L. J Med Chem. 2021 Nov 3. PMID: 34730959.