Activation of autophagy in peripheral blood mononuclear cells in amyotrophic lateral sclerosis
- Authors: Kochergin I.A.1, Tukhvatulin A.I.2, Logunov D.Y.2, Zakharova M.N.1
-
Affiliations:
- Research Center of Neurology
- N.F. Gamaleya Federal Research Center of Epidemiology and Microbiology, the Ministry of Healthcare of the Russian Federation
- Issue: Vol 10, No 4 (2016)
- Pages: 26-31
- Section: Original articles
- Submitted: 30.01.2017
- Published: 02.02.2017
- URL: https://annaly-nevrologii.com/journal/journal/pathID/article/view/17
- DOI: https://doi.org/10.17816/psaic17
- ID: 17
Cite item
Full Text
Abstract
Introduction. Accumulation of intracellular protein aggregates is one of the key processes in pathogenesis of amyotrophic lateral sclerosis (ALS). Autophagy is a complex process during which cell components and organelles are transferred inside lysosomes and are degraded. Autophagy disturbance was found to take place in various neurodegenerative diseases. Autophagy alteration can be observed not only in the central nervous system but also in peripheral blood mononuclear cells (PBMCs). Protein LC3 is the key marker of autophagy.
Objective. To determine protein LC3 concentration in PBMCs of ALS patients and to analyze the relationship between this parameter and clinical characteristics of the disease.
Materials and methods. The study involved 66 patients with definite ALS and 15 healthy volunteers. Past medical history was elicited in all patients; neurological examination and the pulmonary function test were performed. PBMCs were isolated from blood of patients and healthy volunteers. The cells were lysed and subjected to Western blot analysis using anti-LC3 antibodies.
Results. The LC3-I level in PBMCs of ALS patients was increased compared to that in the control group (p<0.001). The LC3-I/LC3-II level was elevated in patients with the lumbosacral form of ALS (stage II ALS and the slow rate of disease progression). The tendency towards increased LC3-II level was observed for the bulbar form and stage III ALS.
Conclusions. The results demonstrated for the first time that PBMCs of ALS patients tend to exhibit a higher level of autophagy activity compared to healthy volunteers.
About the authors
Ivan A. Kochergin
Research Center of Neurology
Author for correspondence.
Email: i.a.kochergin@yandex.ru
Russian Federation, Moscow
A. I. Tukhvatulin
N.F. Gamaleya Federal Research Center of Epidemiology and Microbiology, the Ministry of Healthcare of the Russian Federation
Email: i.a.kochergin@yandex.ru
Russian Federation, Moscow
D. Yu. Logunov
N.F. Gamaleya Federal Research Center of Epidemiology and Microbiology, the Ministry of Healthcare of the Russian Federation
Email: i.a.kochergin@yandex.ru
Russian Federation, Moscow
Maria N. Zakharova
Research Center of Neurology
Email: i.a.kochergin@yandex.ru
Russian Federation, Moscow
References
- Illarioshkin S.N. [The conformational diseases of the brain]. Moscow: Yanus-K; 2003. (in Russ).
- Monahan Z., Shewmaker F., Pandey U.B. Stress granules at the intersection of autophagy and ALS. Brain Res. 2016; 1649(Pt B): 189–200. doi: 10.1016/j.brainres.2016.05.022. PMID: 27181519.
- Lee J.K., Shin J.H., Lee J.E., Choi E.J. Role of autophagy in the pathogenesis of amyotrophic lateral sclerosis. Biochim Biophys Acta. 2015; 1852(11): 2517–24. doi: 10.1016/j.bbadis.2015.08.005. PMID: 26264610.
- Klionsky D.J., Abdelmohsen K., Abe A. et al. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy. 2016; 12(1): 1–222. doi: 10.1080/15548627.2015.1100356. PMID: 26799652.
- Nixon R.A. The role of autophagy in neurodegenerative disease. Nat Med. 2013; 19(8): 983–97. doi: 10.1038/nm.3232. PMID: 23921753.
- Cipolat Mis M.S., Brajkovic S., Frattini E. et al. Autophagy in motor neuron disease: Key pathogenetic mechanisms and therapeutic targets. Mol Cell Neurosci. 2016; 72: 84–90. doi: 10.1016/j.mcn.2016.01.012.PMID: 26837042
- Klyushnikov S.A. [Niemann-Pick disease, type C lysosomal pathology in violation of lipid intracellular transport]. Atmosfera Nervnye bolezni. 2014(1): 4–14. (in Russ).
- Prigione A., Piazza F., Brighina L. et al. Alpha-synuclein nitration and autophagy response are induced in peripheral blood cells from patients with Parkinson disease. Neurosci Lett. 2010; 477(1): 6–10. doi: 10.1016/j.neulet.2010.04.022. PMID: 20399833
- Brooks B.R., Miller R.G., Swash M., Munsat T.L. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2000; 1(5): 293–9. PMID: 11464847.
- Roche J.C., Rojas-Garcia R., Scott K.M. et al. A proposed staging system for amyotrophic lateral sclerosis. Brain 2012; 135(Pt 3): 847–52. doi: 10.1093/brain/awr351. PMID: 22271664.
- Gordon P.H., Miller R.G., Moore D.H. ALSFRS-R. Amyotroph Lateral Scler Other Motor Neuron Disord. 2004; 5 (Suppl 1): 90–3. doi: 10.1080/17434470410019906. PMID: 15512883.
- Bromberg M.B. Nomenclature and Classification of Motor Neuron Disease. Oxford, UK: ‘Oxford University Press’; 2014. doi: 10.1093/med/9780199783113.003.0002.
- Ying Z., Xia Q., Hao Z. et al. TARDBP/TDP-43 regulates autophagy in both MTORC1-dependent and MTORC1-independent manners. Autophagy. 2016; 12(4): 707–8. doi: 10.1080/15548627.2016.1151596. PMID: 27050460.
- Filimonenko M., Stuffers S., Raiborg C. et al. Functional multivesicular bodies are required for autophagic clearance of protein aggregates associated with neurodegenerative disease. J Cell Biol. 2007; 179(3): 485–500. doi: 10.1083/jcb.200702115. PMID: 17984323.
- Morimoto N., Nagai M., Ohta Y. et al. Increased autophagy in transgenic mice with a G93A mutant SOD1 gene. Brain Res. 2007; 1167: 112–7. doi: 10.1016/j.brainres.2007.06.045. PMID: 17689501.
- Sasaki S. Autophagy in spinal cord motor neurons in sporadic amyotrophic lateral sclerosis. J Neuropathol Exp Neurol. 2011; 70(5): 349–59. doi: 10.1097/NEN.0b013e3182160690. PMID: 21487309.
- De Marco G., Lupino E., Calvo A. et al. Cytoplasmic accumulation of TDP-43 in circulating lymphomonocytes of ALS patients with and without TARDBP mutations. Acta Neuropathol. 2011; 121(5): 611–22. doi: 10.1007/s00401-010-0786-7. PMID: 21120508.
- De Marco G., Lomartire A., Calvo A. et al. Monocytes of patients with amyotrophic lateral sclerosis linked to gene mutations display altered TDP-43 subcellular distribution. Neuropathol Appl Neurobiol. 2016. doi: 10.1111/nan.12328. PMID: 27178390.
- Xia Q., Wang H., Hao Z. et al. TDP-43 loss of function increases TFEB activity and blocks autophagosome-lysosome fusion. EMBO J. 2016; 35(2):1 21–42. doi: 10.15252/embj.201591998. PMID: 26702100.
- Xie Y., Zhou B., Lin M.Y., Sheng Z.H. Progressive endolysosomal deficits impair autophagic clearance beginning at early asymptomatic stages in fALS mice. Autophagy 2015; 11(10): 1934–6. doi: 10.1080/15548627.2015.1084460. PMID: 26290961.
- Djeddi A., Michelet X., Culetto E. et al. Induction of autophagy in ESCRT mutants is an adaptive response for cell survival in C. elegans. J Cell Sci. 2012; 125(Pt 3): 685–94. doi: 10.1242/jcs.091702. PMID: 22389403.
- Sala G., Tremolizzo L., Melchionda L. et al. A panel of macroautophagy markers in lymphomonocytes of patients with amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2012; 13(1): 119–24. doi: 10.3109/17482968.2011.611139. PMID: 21916798.
Supplementary files
![](/img/style/loading.gif)