Mical modulates Tau toxicity via cysteine oxidation in vivo

Abstract

Tau accumulation is clearly linked to pathogenesis in Alzheimer’s disease and other Tauopathies. However, processes leading to Tau fibrillization and reasons for its pathogenicity remain largely elusive. Mical emerged as a novel interacting protein of human Tau expressed in Drosophila brains. Mical is characterized by the presence of a flavoprotein monooxygenase domain that generates redox potential with which it can oxidize target proteins. In the well-established Drosophila Tauopathy model, we use genetic interactions to show that Mical alters Tau interactions with microtubules and the Actin cytoskeleton and greatly affects Tau aggregation propensity and Tau-associated toxicity and dysfunction. Exploration of the mechanism was pursued using a Mical inhibitor, a mutation in Mical that selectively disrupts its monooxygenase domain, Tau transgenes mutated at cysteine residues targeted by Mical and mass spectrometry analysis to quantify cysteine oxidation. The collective evidence strongly indicates that Mical’s redox activity mediates the effects on Tau via oxidation of Cys322. Importantly, we also validate results from the fly model in human Tauopathy samples by showing that MICAL1 is up-regulated in patient brains and co-localizes with Tau in Pick bodies. Our work provides mechanistic insights into the role of the Tau cysteine residues as redox-switches regulating the process of Tau self-assembly into inclusions in vivo, its function as a cytoskeletal protein and its effect on neuronal toxicity and dysfunction.

Differential Effects of Human Tau Isoforms to Neuronal Dysfunction and Toxicity in the Drosophila CNS

“…In contrast, PSIM was not affected by the accumulation of any hTau isoform ( Figure 3 B and Supplementary Table S3 ). These results are in agreement with prior reports [ 22 , 32 , 33 ] and expand them to include all hTau isoforms. Importantly, the specificity of consolidated memory defects to PSDM for all 4R isoforms is consistent with the interpretation [ 37 ] that hTau excess of these hTau species in the fly CNS impairs translation-related processes required for PSDM [ 29 , 36 ].…”

“…In agreement with the early appearance of cognitive deficits in human tauopathy patients, associative learning and memory are impaired in Drosophila tauopathy models [ 21 , 22 , 24 , 26 , 27 , 31 , 32 , 33 ]. Given that the MBs are cardinal for these behavioral outputs [ 29 , 30 ] and their size is differentially affected by particular hTau isoforms, we aimed to systematically examine the consequence of all hTau isoforms in associative learning and memory and whether any defects correlate with protein levels, or MB size differences.…”

Distinct microglia alternative splicing in Alzheimer's disease

“…Mical1 was identified as tau interacting protein via proteomic approach. Mical1 changed the interaction properties of tau and potentiated tau toxicity, mediated by Mical1’s redox activity on tau Cys322 [ 19 ]. Moreover, the protein level of Mical1 was increased in AD patients, and considered to be a potential biomarker of tauopathies [ 19 ].…”

“…Mical1 changed the interaction properties of tau and potentiated tau toxicity, mediated by Mical1’s redox activity on tau Cys322 [ 19 ]. Moreover, the protein level of Mical1 was increased in AD patients, and considered to be a potential biomarker of tauopathies [ 19 ]. Add1 plays essential role in dendritic morphology.…”

Correction to: Mical modulates Tau toxicity via cysteine oxidation in vivo

“…Following publication of the original article [ 1 ], it was noted that due to a typesetting mistake, incorrect files for Additional files 6 and 7 were processed.…”