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Loss of Function CHCHD10 Mutations in Cytoplasmic TDP-43 Accumulation and Synaptic Integrity

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Loss of Function CHCHD10 Mutations in Cytoplasmic TDP-43 Accumulation and Synaptic Integrity ARTICLE Received 22 Aug 2016 | Accepted 7 Apr 2017 | Published 6 Jun 2017 DOI: 10.1038/ncomms15558 OPEN Loss of function CHCHD10 mutations in cytoplasmic TDP-43 accumulation and synaptic integrity Jung-A. A. Woo1,2,*, Tian Liu1,2,*, Courtney Trotter1,2,*, Cenxiao C. Fang1,2, Emillio De Narvaez1,2, Patrick LePochat1,2, Drew Maslar1,2, Anusha Bukhari1,2, Xingyu Zhao1,2, Andrew Deonarine3, Sandy D. Westerheide3 & David E. Kang1,2,4 Although multiple CHCHD10 mutations are associated with the spectrum of familial and sporadic frontotemporal dementia–amyotrophic lateral sclerosis (FTD–ALS) diseases, neither the normal function of endogenous CHCHD10 nor its role in the pathological milieu (that is, TDP-43 pathology) of FTD/ALS have been investigated. In this study, we made a series of observations utilizing Caenorhabditis elegans models, mammalian cell lines, primary neurons and mouse brains, demonstrating that CHCHD10 normally exerts a protective role in mitochondrial and synaptic integrity as well as in the retention of nuclear TDP-43, whereas FTD/ALS-associated mutations (R15L and S59L) exhibit loss of function phenotypes in C. elegans genetic complementation assays and dominant negative activities in mammalian systems, resulting in mitochondrial/synaptic damage and cytoplasmic TDP-43 accumulation. As such, our results provide a pathological link between CHCHD10-associated mitochon- drial/synaptic dysfunction and cytoplasmic TDP-43 inclusions. 1 USF Health Byrd Alzheimer’s Institute, University of South Florida, Morsani College of Medicine, Tampa, Florida 33613, USA. 2 Department of Molecular Medicine, University of South Florida, Morsani College of Medicine, Tampa, Florida 33613, USA. 3 Department of Cell Biology, Microbiology & Molecular Biology, University of South Florida, College of Arts and Sciences, Tampa, Florida 33620, USA. 4 James A. Haley Veteran’s Administration Hospital, Tampa, Florida 33612, USA. * These authors contributed equally to this work. Correspondence and requests for materials should be addressed to D.E.K. (email: [email protected]). NATURE COMMUNICATIONS | 8:15558 | DOI: 10.1038/ncomms15558 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/ncomms15558 rontotemporal dementia (FTD) is a progressive neurode- found in a small proportion of ALS and FTLD-TDP, TDP-43 generative disease classically characterized by the selective pathology is associated with the vast majority of ALS and Fdegeneration of the frontal and temporal lobes, associated FTLD4,9. Increasing evidence indicates that TDP-43 is highly with executive impairments, changes in personality and language neurotoxic, in large part, by inducing mitochondrial dysfunction. It is now clear, however, that FTD is frequently dysfunction10–12. Specifically, TDP-43 is co-localized with accompanied by motor neuron disease or amyotrophic lateral mitochondria and reduces mitochondrial length by promoting sclerosis (ALS), and common genetic mutations in multiple genes mitochondrial fission, resulting in mitochondrial transport have been associated with both FTD and ALS1,2. Indeed, B15% defects10. The mitochondrial fusion protein Mfn2 prevents of FTD patients also suffer from ALS, and up to 50% of classical mitochondrial fragmentation, superoxide production and ALS patients also suffer from symptoms of FTD or mild cognitive depolarization (DCm) induced by TDP-43 mutations10, and impairment2. The unifying pathological link between the vast blockade of TDP-43 translocation to mitochondria also blocks majority of ALS and FTD patients is the accumulation of its neurotoxicity12. In line with these observations, TDP-43 cytoplasmic TDP-43 inclusions, the latter in the majority FTD overexpression in transgenic mice increases mitochondrial fission subtype, frontotemporal lobar degeneration with TDP-43 proteins Drp1 and Fis1, reduces the mitochondrial fusion pathology (FTLD-TDP)3,4. protein Mfn1, and promotes mitochondrial fragmentation and TAR DNA-binding protein 43 (TDP-43) is a nuclear protein in aggregation11. the family of heterogeneous ribonucleoproteins (hnRNPs) that Coiled-coil-helix-coiled-coil-helix domain containing 10 plays a major role in regulating RNA splicing, stability and (CHCHD10) encodes a protein that is localized to the transport5. However, in pathological neurons, TDP-43 is often intermembrane space of mitochondria13 associated with the found in the cytoplasm in a ubiquitinated and fragmented form, mitochondrial contact site and cristae organizing system which are prone to aggregation6–8. While TDP-43 mutations are (MICOS) together with mitofusin, mitophilin, CHDHD3 and a R15L 110 20 30 40 CHCHD10 har-1 1 10 20 30 40 50 60 b c d ## n.s. S59L har-1 150 150 N2 43 5070 80 90 ## ## KO CHCHD10 100 100 har-1 61 70 80 90 100 110 50 50 BLPS (% of N2) BBPS (% of N2) 100 110 120 130 142 0 0 CHCHD10 N2 N2 TDP43 TDP43 har-1 har-1 KO har-1 KO 114 120 130 140 154 Identical Conserved Semi-conserved Not conserved ef g h ## N2 har-1 KO TDP43 ## 125 15 ## ** 300 100 10 GFP 75 200 PhC/ N2 5 50 har-1 KO ## % Time curling 100 Percent survival 0 Mitosox (% of N2) 25 0 N2 TDP43 Mitosox N2 0 har-1 KO TDP43 0 10203040 har-1 KO Survival (days since hatched) Figure 1 | Loss of har-1 impairs locomotion mitochondrial health and longevity in C. elegans. (a) Protein sequence alignment between human CHCHD10 and C. elegans har-1. Note that C. elegans har-1 shares 41% identity, 12% conserved similarity, and 18% semi-conserved similarity to human CHCHD10 (http://useast.ensembl.org/index.html). (b–e) Age-synchronized worms per strain (3-day adults: N2, har-1 KO (har-1 À / À ) and TDP43) transferred to fresh NGM plate or M9 buffer and videotaped to measure motility, liquid thrashing rate, and curling behaviour (1-way ANOVA, post hoc Tukey, ##Po0.0001). (b) Motility (measured in BLPS) on NGM plate measured at ambient room temperature (22 °C) and normalized to N2 control from 90 to 94 worms per strain. (c) Liquid thrashing rate (BBPS) measured in M9 buffer at ambient room temperature (22 °C) and normalized to N2 control from 50 worms per strain. (d,e) Representative images of curling posture (red arrows). Per cent time spent curling measured at ambient room temperature (22 °C) from 50 worms per strain (scale bar, 100 mm). (f,g) Age-synchronized worms stained with 5 mM mitosox-red in M9 buffer for 45 min, mounted live on agar pads, imaged by confocal microscopy, quantified with Image J, and normalized to N2 control (one-way ANOVA, **Po0.01, ##Po0.0001, n ¼ 29 worms/ strain, scale bar, 100 mm). Average intensity of head region excluding mouth, pharynx, and intestine quantified. (h) Lifespan analysis (% of worms surviving since days hatching) of N2 and har-1 KO worms at 16 °C (Log-rank Mantel–Cox test, ##Po0.0001, n ¼ 170 worms/strain). All quantitative graphs with error bars were expressed as mean±s.e.m. ANOVA, analysis of variance; KO, knockout. 2 NATURE COMMUNICATIONS | 8:15558 | DOI: 10.1038/ncomms15558 | www.nature.com/naturecommunications NATURE COMMUNICATIONS | DOI: 10.1038/ncomms15558 ARTICLE CHCHD6 (ref. 14). Recent human genetic studies have identified between C. elegans har-1 and human CHCHD10 proteins multiple CHCHD10 mutations in sporadic and familial FTD–ALS (Fig. 1a). To gain insights to the function of CHCHD10 in vivo, spectrum disorders from independent cohorts and ethnic we utilized the VC3169 har-1 À / À C. elegans model (gk3124)to groups13–17, implicating the critical role of mitochondria in assess locomotion in comparison with wild-type N2 ancestral and FTD–ALS diseases. CHCHD10 mutations have also been TDP-43 transgenic strains. TDP-43 expression in the TDP-43 associated with Charcot–Marie–Tooth disease type 2 (ref. 18), transgenic C. elegans CL6049 is driven by the neuron-specific mitochondrial myopathy and spinal muscular atrophy Jokela snb-1 promoter, a strain with impairments in locomotion at room type19. However, despite the role of the FTD/ALS-linked temperature that worsens with heat exposure20. In motility tests CHCHD10 S59L mutation in reducing mitochondrial length at ambient temperature, we observed significantly slower rates of and disorganization of mitochondrial cristae morphology13, movement in both har-1 À / À and TDP-43 transgenic worms by neither the normal function of endogenous CHCHD10 nor the 32 and 80%, respectively, as compared to N2 (Fig. 1b). In liquid nature of the FTD/ALS CHCHD10 mutations has been thrashing tests at ambient temperature, har-1 À / À worms showed investigated. Moreover, whether and how CHCHD10 mutations no significant reduction in body bends per second (BBPS), alter the pathological landscape (that is, TDP-43 inclusions) of whereas the TDP-43 worms displayed a significant 50% reduction FTD–ALS spectrum diseases is completely unknown, and no in BBPS (Fig. 1c). Upon exposure to heat (30 °C for 30 min), both FTD/ALS mutations other than S59L have been functionally TDP-43 and har-1 À / À strains showed dramatically reduced characterized. Here we show in Caenorhabditis elegans models, liquid thrashing rates compared to N2 controls (Supplementary cultured cells, primary neurons, and mouse brains that Fig. 1a), indicating that heat exposure renders the har-1 À / À CHDHD10 normally plays a neuroprotective role and that strain more vulnerable to the loss of har-1 possibly due to FTD/ALS CHCHD10 mutations (R15L and S59L) display loss of proteostatic stress. Next, we tested the strains for the percentage function phenotypes and function in concert with TDP-43 to of time spent in a curled posture in liquid curling tests, since both induce its cytoplasmic mislocalization, resulting in mitochondrial TDP-43 and har-1 À / À worms showed salient abnormalities in and synaptic damage. their pattern of thrashing in liquid (Fig. 1d, Supplementary Fig. 1b and Supplementary Movies 1,2). Interestingly, abnormal curling behaviour increases with age in C. elegans and is reflective Results of a defect in motor coordination21. At ambient temperature, Loss of har-1 loss impairs movement and mitochondria in har-1 À / À and TDP-43 strains showed 4.9-fold and 2.1 increases C.
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