Autophagy Pathways, Ubiquitin-Proteasome System and Neurodegenerative Diseases: a Scopus Review

Resumo

The maintenance of protein homeostasis is essential for neuronal health, and the failure of these mechanisms leads to the accumulation of misfolded proteins, such as α-synuclein, tau and Aβ, which form toxic aggregates, associated with diseases such as Alzheimer's, Parkinson's, Amyotrophic Lateral Sclerosis (ALS) and Huntington's. Protein balance is maintained by a complex network of molecular mechanisms, including chaperones, ubiquitin- proteasome system, autophagy, cellular stress response pathways that ensure the correct folding, degradation and elimination of defective proteins. However, factors such as mutations, environmental and metabolic stress can disrupt this network, in addition to aging, which reduces its effectiveness and performance, resulting in the formation of toxic protein aggregates. This systematic review reinforces the relevance of proteostasis in neuronal health and in the development of neurodegenerative diseases, suggesting that precise modulation of these pathways may be an effective therapeutic approach to slow the progression of these conditions. The work developed is an exploratory study, carried out through a bibliographic research. A literature search was carried out in the Medline, Elsevier, Lilacs and Capes databases of periodicals, published between 2014 and 2024. The selected studies underwent an evaluation of the eligibility criteria. The mechanisms of a proteostasis network were presented in detail and the understanding of these processes reveals new possibilities for treatment of neurodegenerative diseases, opening new perspectives for therapeutic interventions aimed at preserving proteostasis and, consequently, preventing these diseases.

Referências

1. BAJAJ, L. et al. Lysosome biogenesis in health and disease. Journal of Neurochemistry, vol. 148, no. 5, p. 573-589, 2018.
2. BAKER, H.A.; BERNARDINI, J. P. It is not just a phase; quality-controlled ubiquitination of cytosolic proteins. Biochemical Society Transactions, vol. 49, no. 1, p. 365–377, 2021.
3. BALCH, W. E. et al. Adapting proteostasis for disease intervention. Science, vol. 319, no. 5865, p. 916-919, 2008.
4. BALCHIN, D.; HAYER-HARTL, M.; HARTL, F. U. In vivo aspects of protein folding and quality control. Science, vol. 353, no. 6294, p. 871-876, 2016.
5. BARTLETT, A. I.; RADFORD, S. E. An expanding arsenal of experimental methods yields an explosion of insights into protein folding mechanisms. Nature Structural & Molecular Biology, v. 16, no. 6, p. 582–588, 2009.
6. BOURDENX, M. et al. Chaperone-mediated autophagy prevents collapse of the neuronal metastable proteome. Cell, vol. 184, n. 10, p. 2696-2714, 2021.
7. CHITI, F.; DOBSON, C. M. Protein misfolding, amyloid formation, and human disease: a summary of progress over the last decade. Annual Review of Biochemistry, vol. 86, p. 27-68, 2017.
8. DOBSON, C. M. Protein folding and misfolding. Nature, vol. 426, no. 6968, p. 884–890, 2003.
9. FILIPPONE, A. et al. The contribution of altered neuronal autophagy to neurodegeneration. Pharmacology & Therapeutics, vol. 238, p. 108178, 2022.
10. GLICKMAN, M. H.; CIECHANOVER, A. The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiological Reviews, vol. 82, no. 2, p. 373-428, 2002.
11. HETZ, C. Adapting the proteostasis capacity to sustain brain healthspan. Cell, vol. 184, n. 6, p. 1545-1560, 2021.
12. HIPP, M. S.; HARTL, F. U. Interplay of proteostasis capacity and protein aggregation: implications for cellular function and disease. Journal of Molecular Biology, vol. 436, no. 14, p. 168615, 2024.
13. KINGER, S. et al. Molecular chaperones’ potential against defective proteostasis of amyotrophic lateral sclerosis. Cells, vol. 12, no. 9, p. 1302, 2023.
14. LACKIE, R. E. et al. The HSP70/HSP90 chaperone machinery in neurodegenerative diseases. Frontiers in Neuroscience, vol. 11, p. 1-23, 2017.
15. LLEWELLYN, J.; HUBBARD, S. J.; SWIFT, J. Translation as an emerging constraint to protein homeostasis in aging. Trends in Cell Biology, vol. 34, no. 8, p. 646-656, 2024.
16. MOGK, A.; BUKAU, B.; KAMPINGA, H. H. Cellular handling of protein aggregates by disaggregation machines. Molecular Cell, vol. 69, no. 2, p. 214-226, 2018.
17. MONTRESOR, P.; SMITH, J. A.; JONES, R. L. HSP110 is a modulator of amyloid beta (A) aggregation and proteotoxicity. Journal of Neurochemistry, vol. 00, p. 1-19, 2024.
18. PAGE, M. J.; MCKENZIE, J. E.; BOSSUYT, P. M. et al. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 explanation and elaboration: update guidance and exemplars for reporting systematic reviews. British Medical Journal, vol. 372, no. 160, p. 1-36, 2021.
19. SALA, A.J.; BOTT, L. C.; MORIMOTO, L.C. Shaping proteostasis at the cellular, tissue, and organismal level. Journal of Cell Biology, vol. 216, no. 5, p. 1231-1241, 2017.
20. SPENCER, B. et al. Beclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in alpha-synuclein models Parkinson’s and Lewy body diseases. Journal of Neurosciences, vol. 29, no. 43, p. 13578-13588, 2009.
21. TAYLOR, J. P.; DILLIN, A. Aging as an event of proteostasis collapse. Cold Spring Harbor Perspectives in Biology, vol. 3, no. 5, p. a004440, 2011.
22. TYEDMERS, J.; MOGK, A.; BUKAU, B. Cellular strategies for controlling protein aggregation. Nature Reviews Molecular Cell Biology, vol. 11, no. 11, p. 777-788, 2010.
23. UPADHYAY, A. Natural compounds in the regulation of proteostatic pathways: An invincible artillery against stress, aging, and diseases. Acta Pharmaceutica Sinica B, v. 11, no. 10, p. 2995-3014, 2021.
24. VARSHAVSKY, A. The ubiquitin system, autophagy, and regulated protein degradation. Annual Review of Biochemistry, vol. 86, p. 123-128, 2017.
25. WAGNER et al. General loss of proteostasis links Huntington's disease to Cockayne syndrome. Neurobiology of Disease, vol. 201, p. 106668, 2024.
26. YAMAMOTO, K.; YUE, Z. Autophagy and its normal and pathogenic states in the brain. Annual Review of Neuroscience, vol. 37, p. 55-78, 2014.
27. ZATYKA, M.; SARKAR, S.; BARRETT, T. Autophagy in rare (non-lysosomal) neurodegenerative diseases. Journal of Molecular Biology, vol. 432, no. 8, p. 2735-2753, 2020.
28. ZHANG, J.; et al. CaMKII suppresses proteotoxicity by phosphorylating BAG3 in response to proteasomal dysfunction. EMBO Reports, vol. 25, no. 14, p. 4488-4514, 2024.