FUS May Cause Energy Loss in Neurons in ALS

Mitochondria malfunction in ALS. But why these powerhouses fail in motor neurons remains unclear, making the design of energy-boosting therapies for the disease especially challenging (see July 2017 news).

Give me complex V? A new study suggests that ALS-linked mutant FUS interferes with the assembly of ATP synthase complex V in mitochondria, leading to a drop in energy levels in motor neurons. The unfolded protein response is triggered, further damaging these powerhouses, potentially contributing to neurotoxicity (see Martinez et al., 2017). [Courtesy of Deng et al., 2018, Proceedings of the National Academy of Sciences.]

Now, a research team led by Northwestern University’s Jane Wu in Chicago, Illinois reports that ALS-linked FUS interferes with the assembly of a key enzyme complex in mitochondria that produces energy – at least in inducible cellular and fruit fly models of the disease. What’s more, the unfolded protein response in these power plants is activated, potentially further contributing to mitochondrial damage and neurotoxicity.

The enzyme, known as ATP synthase (complex V), is also critical to fold up the inner mitochondrial membrane into “cristae”, key structures that help mitochondria produce energy efficiently.

The results comes at the heels of a previous study, led by King’s College London’s Caroline Vance in England, which found that defects in these power plants could be detected at pre-synaptic nerve terminals in a mouse model of FUS-ALS before the first signs of the disease (So et al., 2018).

The study appeared on September 24 in the Proceedings of the National Academy of Sciences.

The findings add to growing evidence that the buildup of FUS in the cytoplasm of motor neurons contributes to ALS by multiple mechanisms (see August 2013, October 2017, October 2017, March 2018, March 2018, September 2018 news).

Efforts to develop therapies that reduce levels of cytoplasmic FUS in motor neurons are currently underway (see March 2018, April 2018 news).


To learn more about the emerging role of mitochondria in ALS, check out Targeting Mitochondria in ALS: Divide Less and Conquer?


Deng J, Wang P, Chen X, Cheng H, Liu J, Fushimi K, Zhu L, Wu JY. FUS interacts with ATP synthase beta subunit and induces mitochondrial unfolded protein response in cellular and animal models. Proc Natl Acad Sci U S A. 2018 Sep 24. [PubMed].

So E, Mitchell JC, Memmi C, Chennell G, Vizcay-Barrena G, Allison L, Shaw CE, Vance C. Mitochondrial abnormalities and disruption of the neuromuscular junction precede the clinical phenotype and motor neuron loss in hFUSWT transgenic mice. Hum Mol Genet. 2018 Feb 1;27(3):463-474. [PubMed].

Stoica R, Paillusson S, Gomez-Suaga P, Mitchell JC, Lau DH, Gray EH, Sancho RM, Vizcay-Barrena G, De Vos KJ, Shaw CE, Hanger DP, Noble W, Miller CC. ALS/FTD-associated FUS activates GSK-3β to disrupt the VAPB-PTPIP51 interaction and ER-mitochondria associations. EMBO Rep. 2016 Sep;17(9):1326-42. [PubMed].

Martinez BA, Petersen DA, Gaeta AL, Stanley SP, Caldwell GA, Caldwell KA. Dysregulation of the Mitochondrial Unfolded Protein Response Induces Non-Apoptotic Dopaminergic Neurodegeneration in C. elegans Models of Parkinson’s Disease. J Neurosci. 2017 Nov 15;37(46):11085-11100. [PubMed].

Further Reading

Vandoorne T, De Bock K, Van Den Bosch L. Energy metabolism in ALS: an underappreciated opportunity? Acta Neuropathol. 2018 Apr;135(4):489-509. [PubMed].

Vance C, Rogelj B, Hortobágyi T, De Vos KJ, Nishimura AL, Sreedharan J, Hu X, Smith B, Ruddy D, Wright P, Ganesalingam J, Williams KL, Tripathi V, Al-Saraj S, Al-Chalabi A, Leigh PN, Blair IP, Nicholson G, de Belleroche J, Gallo JM, Miller CC, Shaw CE. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science. 2009 Feb 27;323(5918):1208-1211. [PubMed].

Wang WY, Pan L, Su SC, Quinn EJ, Sasaki M, Jimenez JC, Mackenzie IR, Huang EJ, Tsai LH. Interaction of FUS and HDAC1 regulates DNA damage response and repair in neurons. Nat Neurosci. 2013 Oct;16(10):1383-91.  [PubMed].

Deng J, Yang M, Chen Y, Chen X, Liu J, Sun S, Cheng H, Li Y, Bigio EH, Mesulam M, Xu Q, Du S, Fushimi K, Zhu L, Wu JY. FUS Interacts with HSP60 to Promote Mitochondrial Damage. PLoS Genet. 2015 Sep 3;11(9):e1005357. [PubMed].

Yokoi S, Udagawa T, Fujioka Y, Honda D, Okado H, Watanabe H, Katsuno M, Ishigaki S, Sobue G. 3’UTR Length-Dependent Control of SynGAP Isoform α2 mRNA by FUS and ELAV-like Proteins Promotes Dendritic Spine Maturation and Cognitive Function. Cell Rep. 2017 Sep 26;20(13):3071-3084. [PubMed].

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].

Zhang T, Wu YC, Mullane P, Ji YJ, Liu H, He L, Arora A, Hwang HY, Alessi AF, Niaki AG, Periz G, Guo L, Wang H, Elkayam E, Joshua-Tor L, Myong S, Kim JK, Shorter J, Ong SE, Leung AKL, Wang J. FUS Regulates Activity of MicroRNA-Mediated Gene Silencing. Mol Cell. 2018 Mar 1;69(5):787-801.e8. [PubMed].


ATP synthase complex V disease-als mitochondria topic-preclinical
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