Investigating Whether the Improvement of the AMP-Activated Protein Kinase (AmpK) is Neuroprotective in Huntington’s Disease Neurons

Authors

  • Manasa Chillarige University of Pittsburgh

DOI:

https://doi.org/10.5195/pur.2024.45

Abstract

Huntington’s disease (HD) is a hereditary condition which causes disordered movement, behavioral changes, and dementia. As with many neurological diseases, there is no effective treatment and HD is universally fatal. Metformin has been found improve cognitive score in diabetic patients with HD and has also improved motor function and decreased mutant HTT aggregates in mice brains. Like metformin, BC1618 is an inhibitor of Fbxo48 and its potency in stimulating Ampk-dependent signaling greatly exceeds metformin. GA100 also works in a similar manner as BC1618. Thus, Q7 and Q111 cell lines were treated with 5 and 10 μM concentrations of BC1618 or GA1000 and the samples were collected to perform protein, RNA, and DNA analysis. The most significant results from this experiment came from the qPCR results which confirmed the initial hypothesis and supported the idea that both BC1618 and GA100 effectively inhibit Fbxo48 and prolong Ampk activation. We further hypothesize that this will promote mitochondrial biogenesis which can have neuroprotective effects on HD. 

References

Roos RA. Huntington's disease: a clinical review. Orphanet journal of rare diseases.

;5(1):40. doi: 10.1186/1750-1172-5-40. PubMed PMID: 21171977; PMCID: 3022767.

Hervas D, Fornes-Ferrer V, Gomez-Escribano AP, Sequedo MD, Peiro C, Millan JM,

VazquezManrique RP. Metformin intake associates with better cognitive function in patients with Huntington's disease. PLoS One. 2017;12(6):e0179283. Epub 2017/06/21. doi: 10.1371/journal.pone.0179283. PubMed PMID: 28632780; PMCID: PMC5478119.

Sanchis A, Garcia-Gimeno MA, Canada-Martinez AJ, Sequedo MD, Millan JM, Sanz

P,VazquezManrique RP. Metformin treatment reduces motor and neuropsychiatric phenotypes in the zQ175 mouse model of Huntington disease. Experimental & molecular medicine. 2019;51(6):1-16. Epub 2019/06/06. doi: 10.1038/s12276-019-0264-9. PubMed PMID: 31165723; PMCID: PMC6549163.

Liu Y, Jurczak MJ, Lear TB, Lin B, Larsen MB, Kennerdell JR, Chen Y, Huckestein BR,

Nguyen MK, Tuncer F, Jiang Y, Monga SP, O'Donnell CP, Finkel T, Chen BB, Mallampalli RK.

A Fbxo48 inhibitor prevents pAMPKalpha degradation and ameliorates insulin resistance. Nat Chem Biol. 2021;17(3):298-306. Epub 2021/01/27. doi: 10.1038/s41589-020-00723-0. PubMed PMID: 33495648; PMCID: PMC8529588.

Trettel F, Rigamonti D, Hilditch-Maguire P, Wheeler VC, Sharp AH, Persichetti F,

Cattaneo E, MacDonald ME. Dominant phenotypes produced by the HD mutation in

STHdh(Q111) striatal cells. Hum Mol Genet. 2000;9(19):2799-809. PubMed PMID: 11092756.

Milakovic T, Johnson GV. Mitochondrial respiration and ATP production are significantly

impaired in striatal cells expressing mutant huntingtin. J Biol Chem. 2005;280(35):30773-82. doi: 10.1074/jbc.M504749200. PubMed PMID: 15983033.

Yano H, Baranov SV, Baranova OV, Kim J, Pan Y, Yablonska S, Carlisle DL, Ferrante

RJ, Kim AH, Friedlander RM. Inhibition of mitochondrial protein import by mutant huntingtin. Nat Neurosci. 2014;17(6):822-31. doi: 10.1038/nn.3721. PubMed PMID: 24836077.

Jauhari A, Baranov SV, Suofu Y, Kim J, Singh T, Yablonska S, Li F, Wang X, Oberly P,

Minnigh MB, Poloyac SM, Carlisle DL, Friedlander RM. Melatonin inhibits cytosolic mitochondrial DNA-induced neuroinflammatory signaling in accelerated aging and neurodegeneration. J Clin Invest. 2020. Epub 2020/03/18. doi: 10.1172/JCI135026. PubMed PMID: 32182222.

Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time

quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25(4):402-8. doi:

1006/meth.2001.1262. PubMed PMID: 11846609.

Suofu Y, Li W, Jean-Alphonse FG, Jia J, Khattar NK, Li J, Baranov SV, Leronni D,

Mihalik AC, He Y, Cecon E, Wehbi VL, Kim J, Heath BE, Baranova OV, Wang X, Gable MJ, Kretz ES, Di Benedetto G, Lezon TR, Ferrando LM, Larkin TM, Sullivan M, Yablonska S,

Wang J, Minnigh MB, Guillaumet G, Suzenet F, Richardson RM, Poloyac SM, Stolz DB, Jockers R, Witt-Enderby PA, Carlisle DL, Vilardaga JP, Friedlander RM. Dual role of mitochondria in producing melatonin and driving GPCR signaling to block cytochrome c release.

Proc Natl Acad Sci U S A. 2017;114(38):E7997-E8006. doi: 10.1073/pnas.1705768114. PubMed PMID: 28874589; PMCID: PMC5617277.

Baranov SV, Baranova OV, Yablonska S, Suofu Y, Vazquez AL, Kozai TDY, Cui XT,

Ferrando LM, Larkin TM, Tyurina YY, Kagan VE, Carlisle DL, Kristal BS, Friedlander RM. Mitochondria modulate programmed neuritic retraction. Proc Natl Acad Sci U S A. 2019; 116(2):650-9. Epub 2018/12/26. Doi: 10.1073/ pnas. 1811021116. PubMed PMID: 30584104; PMCID: PMC6329959.

Downloads

Published

2024-04-12

How to Cite

Manasa Chillarige. (2024). Investigating Whether the Improvement of the AMP-Activated Protein Kinase (AmpK) is Neuroprotective in Huntington’s Disease Neurons. Pittsburgh Undergraduate Review, 3(1). https://doi.org/10.5195/pur.2024.45

Issue

Vol. 3 No. 1 (2024): Pittsburgh Undergraduate Review

Section

Research

License

Copyright (c) 2024 Manasa Chillarige

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Authors who publish with this journal agree to the following terms:

  1. The Author retains copyright in the Work, where the term “Work” shall include all digital objects that may result in subsequent electronic publication or distribution.
  2. Upon acceptance of the Work, the author shall grant to the Publisher the right of first publication of the Work.
  3. The Author shall grant to the Publisher and its agents the nonexclusive perpetual right and license to publish, archive, and make accessible the Work in whole or in part in all forms of media now or hereafter known under a Creative Commons Attribution 4.0 International License or its equivalent, which, for the avoidance of doubt, allows others to copy, distribute, and transmit the Work under the following conditions:
    1. Attribution—other users must attribute the Work in the manner specified by the author as indicated on the journal Web site;
    with the understanding that the above condition can be waived with permission from the Author and that where the Work or any of its elements is in the public domain under applicable law, that status is in no way affected by the license.
  4. The Author is able to enter into separate, additional contractual arrangements for the nonexclusive distribution of the journal's published version of the Work (e.g., post it to an institutional repository or publish it in a book), as long as there is provided in the document an acknowledgement of its initial publication in this journal.
  5. Authors are permitted and encouraged to post online a prepublication manuscript (but not the Publisher’s final formatted PDF version of the Work) in institutional repositories or on their Websites prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work. Any such posting made before acceptance and publication of the Work shall be updated upon publication to include a reference to the Publisher-assigned DOI (Digital Object Identifier) and a link to the online abstract for the final published Work in the Journal.
  6. Upon Publisher’s request, the Author agrees to furnish promptly to Publisher, at the Author’s own expense, written evidence of the permissions, licenses, and consents for use of third-party material included within the Work, except as determined by Publisher to be covered by the principles of Fair Use.
  7. The Author represents and warrants that:
    1. the Work is the Author’s original work;
    2. the Author has not transferred, and will not transfer, exclusive rights in the Work to any third party;
    3. the Work is not pending review or under consideration by another publisher;
    4. the Work has not previously been published;
    5. the Work contains no misrepresentation or infringement of the Work or property of other authors or third parties; and
    6. the Work contains no libel, invasion of privacy, or other unlawful matter.
  8. The Author agrees to indemnify and hold Publisher harmless from Author’s breach of the representations and warranties contained in Paragraph 6 above, as well as any claim or proceeding relating to Publisher’s use and publication of any content contained in the Work, including third-party content.
  9. The Author agrees to digitally sign the Publisher’s final formatted PDF version of the Work.