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Contributions to Science

Our previous work has contributed to our understanding of (1) an age-dependent attenuation of the HSR, (2) small molecules that support and enhance the HSR, and (3) role of chaperones in the structuring, aggregation and pathogenicity of mHtt in cell models of Huntington’s disease (HD).

(1) Age-dependent and neuron specific attenuation in the HSR

In published work, we showed that induction of HSP chaperones by stress is compromised upon aging and particularly in neuronal cells.   Our observation adds to the theme that proteome quality control is central to the wellbeing of cells to safeguard against “protein conformation” disease, Alzheimer’s, Parkinson’s, and Huntington’s diseases as examples.

  • Liu, A. Y.-C., Lin, Z., Choi, H. S., Sorhage, F. and Li, B. (1989) Attenuated heat shock gene expression in aging diploid fibroblasts. Biol. Chem.  264: 12037-12045.
  • Choi, H. S., Lin, Z., Li, B. and Liu, A. Y.-C. (1990) Age-dependent decrease in the heat-inducible DNA sequence-specific binding activity in human diploid fibroblasts. Biol. Chem., 265: 18005-18011.
  • Liu, A. Y.-C., Lee, Y. K., Manalo, D., and Huang, L. E. (1996) Attenuated heat shock transcriptional response in aging:  Molecular mechanisms and implications in the biology of aging.  In Stress-inducible Cellular Responses  (Ulrich Feige, Richard I. Morimoto, Ichiro Yahara, and Barbara S. Polla, eds.), Birkhauser/Springer.
  • HSF1, Aging and Neurodegeneration. Liu, A Y., Minetti, C.A., Remeta, D.P., Breslauer, K. J. Chen, K. Y. Chapter in upcoming book series “Heat Shock Proteins”, Editors: Punit Kaur, Alexzander A. Asea and Stuart K.  Springer Nature, in press.

 

(2) Identification of small molecule to enhance and support the HSR

Given the critical importance of maintaining the cell proteome in GOOD form, we have worked to identify small molecules and drugs that can support or enhance the activation of HSF1 to induce HSP chaperones for protein QC.  We evaluated the effects of riluzole (the first and only FDA approved drug for the treatment of ALS) and of resveratrol, an activator of the SIRT1 deacetylase, in the regulation and function of HSF1.   Our studies showed that riluzole, by blunting the turnover of HSF1, increased HSF1 reserve and that resveratrol, a small molecule activator of the longevity assurance deacetylase Sirtuin 1 (SIRT1), sustained the activation of HSF1.   Neither riluzole nor resveratrol directly activate HSF1 but significantly enhance the effects of stress in promoting the activation of HSF1 for a more robust response.  Both classes of drugs have been or currently are in clinical trials for various ND conditions, although such efforts have yet to translate to successful therapeutics.

  • Yang JX, Bridges K, Chen KY, Liu AY-C. (2008) Riluzole increases the amount of latent HSF1 for an amplified heat shock response and cytoprotection.   PLoSONE,   3(8):e2864. doi: 10.1371/ journal.pone.0002864.
  • Liu A Y-C, Mathur R, Mei N, Langhammer CG, Babiarz B, and Firestein BL. (2011) The neuroprotective drug riluzole amplifies the heat shock factor 1 (HSF1)- and glutamate transporter 1 (GLT1)-dependent cytoprotective mechanisms for neuronal survival. Biol. Chem. 286: 2785-2794.
  • Diana J. Liu, David Hammer, Daniel Komlos, Kuang Yu Chen, Bonnie L. Firestein, and Alice Y.-C. Liu. (2014) SIRT1 knockdown promotes neural differentiation and attenuates the heat shock response. Cellular Physiology 229: 1224–1235.

(3)  Structuring, aggregation vis-a-vis pathogenicity of polyQ-expanded huntingtin

Q represents the amino acid “glutamine”, and a contiguous string of “Q” in proteins is often used as a motif for protein binding/recognition/signaling.  PolyQ expansion of key regulatory proteins is associated with 9 different neurodegenerative diseases, with Huntington’s disease (HD) being a prime example.  PolyQ-expanded mHttexon1 is an intrinsically disordered protein (IDP), and in cells it assumes a variety of conformations and can aggregate to form “inclusion bodies”.  A long unresolved question in HD is “which of these mHtt conformers is pathogenic?”  This is an critically important issue with significant implications in framing therapeutics development for HD.  In our recent studies, we showed that conditions that promote protein structuring – including the increased expression of HSP chaperones or the addition of osmolytes – promote the aggregation of mHtt to form inclusion body (IB) and alleviates transcription factor dysfunction to promote neuron survival. Our work along with a string of observations from other laboratories suggest that it is primarily the low molecular weight entities of mHtt that drives HD pathogenesis.

  • Justin Y. Chen, Miloni Parekh, Hadear Seliman, Dariya Bakshinskaya, Wei Dai, Kelvin Kwan, Kuang Yu Chen, and Alice Y. C. Liu. Heat Shock Promotes Mutant Huntingtin Inclusion Body Formation and Alleviates Transcription Factor Dysfunction. (2018) J. Biological Chemistry 293:15581-15593. DOI 10.1074/jbc.RA118.002933
  • Osmolytes dynamically regulate mutant Huntingtin aggregation and CREB function in Huntington’s disease cell models. Shreyaas Aravindan, Samantha Chen, Hannaan Choudhry, Celine Molfetta, Kuang Yu Chen & Alice Y. C . Liu*. Scientific Reports 10:15511. https://doi.org/10.1038/s41598-020-72613-3