Macroautophagy Abnormality in Essential Tremor
Open Access
- 27 December 2012
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 7 (12), e53040
- https://doi.org/10.1371/journal.pone.0053040
Abstract
Macroautophagy is a cellular mechanism for the clearance of protein aggregates and damaged organelles. Impaired macroautophagy has been observed in neurodegenerative disorders. We investigated the macroautophagy pathway in essential tremor (ET) cases compared to age-matched controls. We analyzed microtubule-associated protein light chain 3-II (LC3-II), S6K, phosphorylated S6K, beclin-1, and mitochondrial membrane proteins levels by Western blot in the post-mortem cerebellum of 10 ET cases and 11 controls. We also performed immunohistochemistry in 12 ET cases and 13 controls to quantify LC3 clustering in Purkinje cells (PCs). LC3-II protein levels were significantly lower in ET cases vs. controls on Western blot (0.84±0.14 vs. 1.00±0.14, p = 0.02), and LC3-II clustering in PCs by immunohistochemistry was significantly lower in ET cases vs. controls (2.03±3.45 vs. 8.80±9.81, p = 0.03). In ET cases, disease duration was inversely correlated with LC3-II protein level (r = −0.64, p = 0.046). We found that mitochondrial membrane proteins were accumulated in ET (TIM23: 1.36±0.11 in ET cases vs. 1.00±0.08 in controls, p = 0.02; TOMM20: 1.63±0.87 in ET cases vs. 1.00±0.14 in controls, p = 0.03). Beclin-1, which is involved in macroautophagy, was strikingly deficient in ET (0.42±0.13 vs. 1.00±0.35, p<0.001). Decreased macroautophagy was observed in the ET cerebellum, and this could be due to a decrease in beclin-1 levels, which subsequently lead to mitochondrial accumulation as a result of autophagic failure. This provides a possible means by which perturbed macroautophagy could contribute to PC pathology in ET.This publication has 40 references indexed in Scilit:
- Beclin 1 Gene Transfer Activates Autophagy and Ameliorates the Neurodegenerative Pathology in α-Synuclein Models of Parkinson's and Lewy Body DiseasesJournal of Neuroscience, 2009
- Essential TremorsArchives of Neurology, 2009
- Metabolic Activity Determines Efficacy of Macroautophagic Clearance of Pathological Oligomeric α-SynucleinThe American Journal of Pathology, 2009
- Autophagy activation and enhanced mitophagy characterize the Purkinje cells of pcd mice prior to neuronal deathMolecular Brain, 2009
- Dynamics and diversity in autophagy mechanisms: lessons from yeastNature Reviews Molecular Cell Biology, 2009
- Acetylation Targets Mutant Huntingtin to Autophagosomes for DegradationCell, 2009
- Chapter 11 Autophagy in Neurite Injury and NeurodegenerationMethods in Enzymology, 2009
- Structural study of Purkinje cell axonal torpedoes in essential tremorNeuroscience Letters, 2009
- The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid β accumulation in miceJCI Insight, 2008
- Twenty-first century brain banking. Processing brains for research: the Columbia University methodsActa Neuropathologica, 2007