title: Macroautophagy abnormality in essential tremor.
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.
authors.affiliation: Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York, United States of America.
authors.forename: Sheng-Han
authors.initials: SH
authors.lastname: Kuo
authors.forename: Guomei
authors.initials: G
authors.lastname: Tang
authors.forename: Karen
authors.initials: K
authors.lastname: Ma
authors.forename: Rachel
authors.initials: R
authors.lastname: Babij
authors.forename: Etty
authors.initials: E
authors.lastname: Cortes
authors.forename: Jean-Paul G
authors.initials: JP
authors.lastname: Vonsattel
authors.forename: Phyllis L
authors.initials: PL
authors.lastname: Faust
authors.forename: David
authors.initials: D
authors.lastname: Sulzer
authors.forename: Elan D
authors.initials: ED
authors.lastname: Louis
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000502:physiology*; D000071186:Beclin-1; D016022:Case-Control Studies; D002531:Cerebellum / Q000378:metabolism* / Q000473:pathology; D020329:Essential Tremor / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011689:Purkinje Cells / Q000378:metabolism* / Q000473:pathology
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C477012:MAP1LC3A protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins