Guo W, Naujock M, Fumagalli L, Vandoorne T, Baatsen P, Boon R, Ordovás L, Patel A, Welters M, Vanwelden T, Geens N, Tricot T, Benoy V, Steyaert J, Lefebvre-Omar C, Boesmans W, Jarpe M, Sterneckert J, Wegner F, Petri S, Bohl D, Vanden Berghe P, Robberecht W, Van Damme P, Verfaillie C, Van Den Bosch L. HDAC6 inhibition reverses axonal transport defects in motor neurons derived from FUS-ALS patients. Nat Commun. 2017 Oct 11;8(1):861. PubMed.
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This is a well-performed study in part because the authors generated multiple iPSC lines from four ALS patients harboring different FUS mutations. More importantly, they generated one pair of isogenic lines with one corrected point mutation to confirm their key findings. Thus, their results are convincing and not due to clonal variations between different iPSC lines. Another important finding is that the observed axonal transport defects can be rescued by HDAC6 inhibition. Defects in this very important cellular pathway have been implicated in ALS pathogenesis before. Thus, their study suggests a novel therapeutic approach. It will be interesting in the future to test whether this therapeutic approach works or not in animal models of ALS.
View all comments by Fen-Biao GaoThe issue of axonal transport in the context of ALS is relevant given the extreme polarization of motor neurons. Even subtle defects in transport would affect the delivery of cargo to (e.g., structural synaptic components, mitochondria, etc.) and transport of cargo from synapses (e.g., autophagosomes) that are frequently seen disrupted in ALS. Creating motor neurons from FUS mutation carriers, the Van Den Bosch group at VIB and KU Leuven not only shows FUS-related pathology in the cytoplasm but also axonal trafficking defects. An important question in many neurodegenerative diseases is that of cell type specificity. While this work does not provide an explanation of why FUS affects motor neurons, the work does show the defects are at least present in motor neurons derived from patient cells, a discovery in and of itself very exciting. However, if this defect is specific to motor neurons remains an open question, as in this work other types of neurons were not tested.
The authors go a long way to control their experimental set-up: Using rescue experiments as well as expression of FUS in human embryonic stem cells, they show axonal transport defects are dependent on the presence of the FUS mutation. What is exciting is that HDAC6 inhibition restores the transport defects. The reason for this is that deacetylation of microtubuli is inhibited and acetylated microtubuli are a better substrate for motor-driven transport. The ability of HDAC6-inhibition to rescue ALS-related phenotypes is similar to reports of this group on the use of HDAC6 inhibitors in other disease conditions and also in the context of Drosophila models of ALS, where we found that loss of HDAC6 is protective (Miskiewicz et al., 2014). Hence, it is interesting that HDAC6 is emerging as a broadly applicable tool to promote axonal transport.
Open questions include if transport defects are truly pathogenic in the context of disease. At least in the context of human motor neurons with FUS mutations, the transport defects do occur, but what is still unclear is if they are causal to aspects of the pathology. Another open question is if acetylation of other HDAC6 targets (besides tubulin) contributes to the rescue of FUS-related defects. HDAC6 is a cytoplasmic deacetylase and other targets exist as well. It will be interesting (and important in the context of therapy) to assess if they contribute to disease modification as well.
References:
Miskiewicz K, Jose LE, Yeshaw WM, Valadas JS, Swerts J, Munck S, Feiguin F, Dermaut B, Verstreken P. HDAC6 is a Bruchpilot deacetylase that facilitates neurotransmitter release. Cell Rep. 2014 Jul 10;8(1):94-102. Epub 2014 Jun 26 PubMed.
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