The role of mitochondria in pathogenesis of Huntington´s disease
Authors:
M. Marková; H. Hansíková
Authors‘ workplace:
Laboratoř pro studium mitochondriálních poruch, Klinika dětského a dorostového lékařství, 1. lékařská fakulta Univerzity Karlovy v Praze a Všeobecná fakultní nemocnice v Praze
Published in:
Klin. Biochem. Metab., 24, 2016, No. 1, p. 27-31
Overview
Huntington´s disease (HD) is an inherited neurodegenerative disease caused by an extended portion of CAG repeats induced higher number of repetitions in the first exon of the gene for huntingtin (Htt), which leads to changes in function of the protein. Most marked neuropathological manifestation of the disease is the loss of striatal neurons. The exact mechanisms responsible for neuronal death have not yet been sufficiently explained. In recent years increasing number of scientific studies that point out that this process plays important role in disruption of mitochondrial function and related impaired energy metabolism. This review is focused to the most striking mitochondrial defects caused by influence of mutated form of huntingtin. Broad spectrum of changes in mitochondrial function includes disruption of mitochondrial biogenesis, mitochondrial Ca2+ homeostasis, increased oxidative stress, changes in mitochondrial dynamics and many other processes. The combination of these aspects seems to contribute to the death of striatal neurons in HD.
Keywords:
mitochondria, oxidative phosphorylation system, Huntington’s disease, huntingtin.
Sources
1. Ho, L. W., Carmichael, J., Swartz, J., Wyttenbach, A., Rankin, J., Rubinsztein, D. C. The molecular bio-logy of Huntington’s disease. Psychological medicine, 2001, vol. 31, no. 1, p. 3–14.
2. Bates, G. P. History of genetic disease: the molecular genetics of Huntington disease - a history. Nature reviews, Genetics, 2005, vol. 6, no. 10, p. 766–73.
3. Telenius, H., Kremer, H. P., Theilmann, J. et al. Molecular analysis of juvenile Huntington disease: the major influence on (CAG)n repeat length is the sex of the affected parent. Human molecular genetics, 1993, vol. 2, no. 10, p. 1535–40.
4. MacDonald, M. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell, 1993, vol. 72, no. 6, p. 971–983.
5. Duyao, M., Ambrose, C., Myers, R. et al. Trinucleotide repeat length instability and age of onset in Huntington’s disease. Nature Genetics, 1993, vol. 4, no. 4, p. 387–392.
6. McKinstry, S. U., Karadeniz, Y. B., Worthington, A. K. et al. Huntingtin is required for normal excitatory synapse development in cortical and striatal circuits. The Journal of neuroscience: the official journal of the Society for Neuroscience, 2014, vol. 34, no. 28, p. 9455–72.
7. Sharp, A. H., Loev, S. J., Schilling, G. et al. Widespread expression of Huntington’s disease gene (IT15) protein product. Neuron, 1995, vol. 14, no. 5, p. 1065–1074.
8. Costa, V. and Scorrano, L. Shaping the role of mitochondria in the pathogenesis of Huntington’s disease. The EMBO journal, 2012, vol. 31, no. 8, p. 1853–64.
9. Damiano, M., Galvan, L., Déglon, N., Brouillet, E. Mitochondria in Huntington’s disease. Biochimica et biophysica acta, 2010, vol. 1802, no. 1, p. 52–61.
10. Lin, M. T. and Beal, M. F. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature, 2006, vol. 443, no. 7113, p. 787–95.
11. Pickrell, A. M., Fukui, H., Wang, X., Pinto, M., Moraes, C. T. The striatum is highly susceptible to mitochondrial oxidative phosphorylation dysfunctions. The Journal of neuroscience: the official journal of the Society for Neuroscience, 2011, vol. 31, no. 27, p. 9895–904.
12. Lin, J., Wu, P.-H., Tarr, P. T. et al. Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1alpha null mice. Cell, 2004, vol. 119, no. 1, p. 121–35.
13. Cui, L., Jeong, H., Borovecki, F., Parkhurst, C. N., Tanese, N., Krainc, D. Transcriptional repression of PGC-1alpha by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration. Cell, 2006, vol. 127, no. 1, p. 59–69.
14. Panov, A. V., Gutekunst, C.-A., Leavitt, B. R. et al. Early mitochondrial calcium defects in Huntington’s disease are a direct effect of polyglutamines. Nature neuroscience, 2002, vol. 5, no. 8, p. 731–6.
15. Nicholls, D. G. Mitochondrial calcium function and dysfunction in the central nervous system. Biochimica et biophysica acta, 2009, vol. 1787, no. 11, p. 1416–24.
16. Choo, Y. S., Johnson, G. V. W., MacDonald, M., Detloff, P. J., Lesort, M. Mutant huntingtin directly increa-ses susceptibility of mitochondria to the calcium-induced permeability transition and cytochrome c release. Human molecular genetics, 2004, vol. 13, no. 14, p. 1407–20.
17. Tabrizi, S. J., Cleeter, M. W., Xuereb, J., Taanman, J. W., Cooper, J. M., Schapira, A. H. Biochemical abnormalities and excitotoxicity in Huntington’s disease brain. Annals of neurology, 1999, vol. 45, no. 1, p. 25–32.
18. Gardner, P. R., Raineri, I., Epstein, L. B., White C. W. Superoxide Radical and Iron Modulate Aconitase Acti-vity in Mammalian Cells. Journal of Biological Chemistry, 1995, vol. 270, no. 22, p. 13399–13405.
19. Sohal, R. S. and Brunk, U. T. Lipofuscin as an indicator of oxidative stress and aging. Advances in experimental medicine and biology, 1989, vol. 266, p. 17–26; discussion 27–9.
20. Tellez-Nagel, I., Johnson, A. B., Terry R. D. Studies on brain biopsies of patients with Huntington’s chorea. Journal of neuropathology and experimental neurology, 1974, vol. 33, no. 2, p. 308–32.
21. Sorolla, M. A., Reverter-Branchat, G., Tamarit, J., Ferrer, I., Ros, J., Cabiscol E. Proteomic and oxidative stress analysis in human brain samples of Huntington disease. Free radical biology & medicine, 2008, vol. 45, no. 5, p. 667–78.
22. Gu, M., Gash, M. T., Mann, V. M., Javoy-Agid, F., Cooper, J. M., Schapira, A. H. Mitochondrial defect in Huntington’s disease caudate nucleus. Annals of neuro-logy, 1996, vol. 39, no. 3, p. 385–9.
23. Damiano, M., Diguet, E., Malgorn, C. et al. A role of mitochondrial complex II defects in genetic models of Huntington’s disease expressing N-terminal fragments of mutant huntingtin. Human molecular genetics, 2013, vol. 22, no. 19, p. 3869–82.
24. Benchoua, A., Trioulier, Y., Zala, D. et al. Involvement of mitochondrial complex II defects in neuronal death produced by N-terminus fragment of mutated huntingtin. Molecular biology of the cell, 2006, vol. 17, no. 4, p. 1652–63.
25. Yano, H., Baranov, S. V., Baranova, O. V. et al. Inhibition of mitochondrial protein import by mutant huntingtin. Nature Neuroscience, 2014, vol. 17, no. 6, p. 822–831.
26. Squitieri, F., Falleni, A., Cannella, M. et al. Abnormal morphology of peripheral cell tissues from patients with Huntington disease. Journal of neural transmission (Vienna, Austria: 1996), 2010, vol. 117, no. 1, p. 77–83.
27. van der Bliek, A. M., Shen, Q., Kawajiri, S. Mechanisms of mitochondrial fission and fusion. Cold Spring Harbor perspectives in biology, 2013, vol. 5, no. 6, p. a011072.
28. Kim, J., Moody, J. P., Edgerly, C. K. et al. Mitochondrial loss, dysfunction and altered dynamics in Huntington’s disease. Human molecular genetics, 2010, vol. 19, no. 20, p. 3919–35.
29. Song, W., Chen, J., Petrilli, A. et al. Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity. Nature medicine, 2011, vol. 17, no. 3, p. 377–82.
30. Shirendeb, U., Reddy, A. P., Manczak, M. et al. Abnormal mitochondrial dynamics, mitochondrial loss and mutant huntingtin oligomers in Huntington’s disease: implications for selective neuronal damage. Human molecular genetics, 2011, vol. 20, no. 7, p. 1438–55.
31. Wang, H., Lim, P. J., Karbowski, M., Monteiro, M. J. Effects of overexpression of huntingtin proteins on mitochondrial integrity. Human molecular genetics, 2009, vol. 18, no. 4, p. 737–52.
32. Orr, A. L., Li, S., Wang, C.-E. et al. N-terminal mutant huntingtin associates with mitochondria and impairs mitochondrial trafficking. The Journal of neuroscience: the official journal of the Society for Neuroscience, 2008, vol. 28, no. 11, p. 2783–92.
33. Bossy-Wetzel, E., Petrilli, A., Knott, A. B. Mutant huntingtin and mitochondrial dysfunction. Trends in neurosciences, 2008, vol. 31, no. 12, p. 609–16.
34. Chang, D. T. W., Rintoul, G. L., Pandipati, S., Reynolds, I. J. Mutant huntingtin aggregates impair mitochondrial movement and trafficking in cortical neurons. Neurobiology of disease, 2006, vol. 22, no. 2, p. 388–400.
35. Kim, S. and Kim, K.-T. Therapeutic Approaches for Inhibition of Protein Aggregation in Huntington’s Disease. Experimental neurobiology, 2014, vol. 23, no. 1, p. 36–44.
Labels
Clinical biochemistry Nuclear medicine Nutritive therapistArticle was published in
Clinical Biochemistry and Metabolism
2016 Issue 1
Most read in this issue
- Antibody structure and its reactivity.
- Criteria of analytical quality measurement in clinical biochemistry. Current international consensus and its implications for routine action of clinical laboratories.
- Influence of IGF1 (insulin-like growth factor 1) signaling pathway to the development of cancer diseases
- IGF1 (insulin-like growth factor 1), basic characteristics, biological effect, age and gender dependence