Loss of MEC-17 Leads to Microtubule Instability and Axonal Degeneration

Abstract

SUMMARY Axonal degeneration arises as a consequence of neuronal injury and is a common hallmark of a number of neurodegenerative diseases. However, the genetic causes and the cellular mechanisms that trigger this process are still largely unknown. Based on forward genetic screening in C. elegans, we have identified the α-tubulin acetyltransferase gene mec-17 as causing spontaneous, adult-onset, and progressive axonal degeneration. Loss of MEC-17 leads to microtubule instability, a reduction in mitochondrial number, and disrupted axonal transport, with altered distribution of both mitochondria and synaptic components. Furthermore, mec-17-mediated axonal degeneration occurs independently from its acetyltransferase domain; is enhanced by mutation of coel-1, a tubulin-associated molecule; and correlates with the animal’s body length. This study therefore identifies a critical role for the conserved microtubule-associated protein MEC-17 in preserving axon integrity and preventing axonal degeneration.

Epothilone B Benefits Nigrostriatal Pathway Recovery by Promoting Microtubule Stabilization After Intracerebral Hemorrhage

“…Interestingly, αTAT1 (also known as MEC‐17) is a specific acyltransferase that promotes α‐tubulin acetylation on lysine 40 (K40), and many studies have verified that elevated levels of acetylated α‐tubulin are a marker of stable microtubules 35, 36. Furthermore, this study also revealed that the loss of MEC‐17 (αTAT1) expression leads to microtubule instability, axonal degeneration, and disrupted axonal transport in Caenorhabditis elegans 37. In addition, MEC‐17 (αTAT1) deficiency leads to reduced α‐tubulin acetylation and impaired migration of cortical neurons in mice 38.…”

Structure, function, and regulation of mitofusin‐2 in health and disease

“…Indeed, mouse and zebrafish models of CMT2A have provided crucial information on the importance of Mfn2 in normal physiology and disease (Detmer et al, 2008;Vettori et al, 2011;Chapman et al, 2013;Bannerman et al, 2016). Moreover, recent studies in small model organisms such as the fruit fly Drosophila melanogaster and the nematode Caenorhabditis elegans have been instrumental in characterizing the role of mitochondria in neuronal health (Neumann & Hilliard, 2014;Rawson et al, 2014;Babic et al, 2015;Neumann et al, 2015;Melkov et al, 2016;Morsci et al, 2016;Yu et al, 2016). However, despite this progress, several outstanding questions and major goals for future research remain and are outlined below.…”

Next-Generation Sequencing-Based Approaches for Mutation Mapping and Identification in Caenorhabditis elegans

“…The main disadvantage of EMS-density mapping is lower mapping resolution owing to the lower density of EMSinduced SNPs and the inability to use allele frequencies across the chromosome for refining the mapping region. EMS-density mapping has successfully been used to clone numerous mutants (Zuryn et al 2010(Zuryn et al , 2014Svensk et al 2013;Neumann and Hilliard 2014;Steciuk et al 2014;Tocchini et al 2014;Rauthan et al 2015).…”