Modelling TDP-43 proteinopathy in Drosophila uncovers shared and neuron-specific targets across ALS and FTD relevant circuits

Arai T, Hasegawa M, Akiyama H, Ikeda K, Nonaka T, Mori H, Mann D, Tsuchiya K, Yoshida M, Hashizume Y et al (2006) TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 351:602–611. https://doi.org/10.1016/j.bbrc.2006.10.093 Ferrari R, Kapogiannis D, Huey ED, Momeni P (2011) FTD and ALS: a tale of two diseases. Curr Alzheimer Res 8:273–294. https://doi.org/10.2174/156720511795563700 Ling SC, Polymenidou M, Cleveland DW (2013) Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Neuron 79:416–438. https://doi.org/10.1016/j.neuron.2013.07.033 Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM et al (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133. https://doi.org/10.1126/science.1134108 Mackenzie IR, Bigio EH, Ince PG, Geser F, Neumann M, Cairns NJ, Kwong LK, Forman MS, Ravits J, Stewart H et al (2007) Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations. Ann Neurol 61:427–434. https://doi.org/10.1002/ana.21147 Cairns NJ, Neumann M, Bigio EH, Holm IE, Troost D, Hatanpaa KJ, Foong C, White CL 3rd, Schneider JA, Kretzschmar HA et al (2007) TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions. Am J Pathol 171:227–240. https://doi.org/10.2353/ajpath.2007.070182 Kabashi E, Valdmanis PN, Dion P, Spiegelman D, McConkey BJ, Vande Velde C, Bouchard JP, Lacomblez L, Pochigaeva K, Salachas F et al (2008) TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet 40:572–574. https://doi.org/10.1038/ng.132 Rutherford NJ, Zhang YJ, Baker M, Gass JM, Finch NA, Xu YF, Stewart H, Kelley BJ, Kuntz K, Crook RJ et al (2008) Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis. PLoS Genet 4:e1000193. https://doi.org/10.1371/journal.pgen.1000193 Sreedharan J, Blair IP, Tripathi VB, Hu X, Vance C, Rogelj B, Ackerley S, Durnall JC, Williams KL, Buratti E et al (2008) TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319:1668–1672. https://doi.org/10.1126/science.1154584 Borroni B, Bonvicini C, Alberici A, Buratti E, Agosti C, Archetti S, Papetti A, Stuani C, Di Luca M, Gennarelli M et al (2009) Mutation within TARDBP leads to Frontotemporal Dementia without motor neuron disease. Hum Mutat 30:E974–E983. https://doi.org/10.1002/humu.21100 Chen HJ, Topp SD, Hui HS, Zacco E, Katarya M, McLoughlin C, King A, Smith BN, Troakes C, Pastore A et al (2019) RRM adjacent TARDBP mutations disrupt RNA binding and enhance TDP-43 proteinopathy. Brain 142:3753–3770. https://doi.org/10.1093/brain/awz313 Al-Chalabi A, Jones A, Troakes C, King A, Al-Sarraj S, van den Berg LH (2012) The genetics and neuropathology of amyotrophic lateral sclerosis. Acta Neuropathol 124:339–352. https://doi.org/10.1007/s00401-012-1022-4 Chang X-L, Tan M-S, Tan L, Yu J-T (2015) The Role of TDP-43 in Alzheimer’s Disease. Mol Neurobiol 53:3349–3359. https://doi.org/10.1007/s12035-015-9264-5 Josephs KA, Whitwell JL, Weigand SD, Murray ME, Tosakulwong N, Liesinger AM, Petrucelli L, Senjem ML, Knopman DS, Boeve BF et al (2014) TDP-43 is a key player in the clinical features associated with Alzheimer’s disease. Acta Neuropathol 127:811–824. https://doi.org/10.1007/s00401-014-1269-z Rohn TT (2008) Caspase-cleaved TAR DNA-binding protein-43 is a major pathological finding in Alzheimer’s disease. Brain Res 1228:189–198. https://doi.org/10.1016/j.brainres.2008.06.094 McAleese KE, Walker L, Erskine D, Thomas AJ, McKeith IG, Attems J (2017) TDP-43 pathology in Alzheimer’s disease, dementia with Lewy bodies and ageing. Brain Pathol 27:472–479. https://doi.org/10.1111/bpa.12424 Hasegawa M, Arai T, Akiyama H, Nonaka T, Mori H, Hashimoto T, Yamazaki M, Oyanagi K (2007) TDP-43 is deposited in the Guam parkinsonism-dementia complex brains. Brain 130:1386–1394. https://doi.org/10.1093/brain/awm065 Amador-Ortiz C, Lin WL, Ahmed Z, Personett D, Davies P, Duara R, Graff-Radford NR, Hutton ML, Dickson DW (2007) TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer’s disease. Ann Neurol 61:435–445. https://doi.org/10.1002/ana.21154 Josephs KA, Murray ME, Whitwell JL, Parisi JE, Petrucelli L, Jack CR, Petersen RC, Dickson DW (2014) Staging TDP-43 pathology in Alzheimer’s disease. Acta Neuropathol 127:441–450. https://doi.org/10.1007/s00401-013-1211-9 Meneses A, Koga S, O’Leary J, Dickson DW, Bu G, Zhao N (2021) TDP-43 pathology in Alzheimer’s disease. Mol Neurodegener 16:84. https://doi.org/10.1186/s13024-021-00503-x Mackenzie IR, Neumann M, Baborie A, Sampathu DM, Du Plessis D, Jaros E, Perry RH, Trojanowski JQ, Mann DM, Lee VM (2011) A harmonized classification system for FTLD-TDP pathology. Acta Neuropathol 122:111–113. https://doi.org/10.1007/s00401-011-0845-8 Gao J, Wang L, Huntley ML, Perry G, Wang X (2018) Pathomechanisms of TDP-43 in neurodegeneration. J Neurochem. https://doi.org/10.1111/jnc.14327 Jo M, Lee S, Jeon YM, Kim S, Kwon Y, Kim HJ (2020) The role of TDP-43 propagation in neurodegenerative diseases: integrating insights from clinical and experimental studies. Exp Mol Med 52:1652–1662. https://doi.org/10.1038/s12276-020-00513-7 Swain A, Misulovin Z, Pherson M, Gause M, Mihindukulasuriya K, Rickels RA, Shilatifard A, Dorsett D (2016) Drosophila TDP-43 RNA-binding protein facilitates association of sister chromatid cohesion proteins with genes, enhancers and polycomb response elements. PLoS Genet 12:e1006331. https://doi.org/10.1371/journal.pgen.1006331 Fiesel FC, Weber SS, Supper J, Zell A, Kahle PJ (2012) TDP-43 regulates global translational yield by splicing of exon junction complex component SKAR. Nucl Acids Res 40:2668–2682. https://doi.org/10.1093/nar/gkr1082 Freibaum BD, Chitta RK, High AA, Taylor JP (2010) Global analysis of TDP-43 interacting proteins reveals strong association with RNA splicing and translation machinery. J Proteome Res 9:1104–1120. https://doi.org/10.1021/pr901076y Ling JP, Pletnikova O, Troncoso JC, Wong PC (2015) TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD. Science 349:650–655. https://doi.org/10.1126/science.aab0983 Polymenidou M, Lagier-Tourenne C, Hutt KR, Huelga SC, Moran J, Liang TY, Ling S-C, Sun E, Wancewicz E, Mazur C et al (2011) Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43. Nat Neurosci 14:459–468. https://doi.org/10.1038/nn.2779 Tollervey JR, Curk T, Rogelj B, Briese M, Cereda M, Kayikci M, König J, Hortobágyi T, Nishimura AL, Župunski V et al (2011) Characterizing the RNA targets and position-dependent splicing regulation by TDP-43. Nat Neurosci 14:452–458. https://doi.org/10.1038/nn.2778 Alami NH, Smith RB, Carrasco MA, Williams LA, Winborn CS, Han SS, Kiskinis E, Winborn B, Freibaum BD, Kanagaraj A et al (2014) Axonal transport of TDP-43 mRNA granules is impaired by ALS-causing mutations. Neuron 81:536–543. https://doi.org/10.1016/j.neuron.2013.12.018 Chou C-C, Zhang Y, Umoh ME, Vaughan SW, Lorenzini I, Liu F, Sayegh M, Donlin-Asp PG, Chen YH, Duong DM et al (2018) TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD. Nat Neurosci 21:228–239. https://doi.org/10.1038/s41593-017-0047-3 Fallini C, Bassell GJ, Rossoll W (2012) The ALS disease protein TDP-43 is actively transported in motor neuron axons and regulates axon outgrowth. Hum Mol Genet 21:3703–3718. https://doi.org/10.1093/hmg/dds205 Colombrita C, Zennaro E, Fallini C, Weber M, Sommacal A, Buratti E, Silani V, Ratti A (2009) TDP-43 is recruited to stress granules in conditions of oxidative insult. J Neurochem 111:1051–1061. https://doi.org/10.1111/j.1471-4159.2009.06383.x Khalfallah Y, Kuta R, Grasmuck C, Prat A, Durham HD, Vande Velde C (2018) TDP-43 regulation of stress granule dynamics in neurodegenerative disease-relevant cell types. Sci Rep 8:7551. https://doi.org/10.1038/s41598-018-25767-0 McDonald KK, Aulas A, Destroismaisons L, Pickles S, Beleac E, Camu W, Rouleau GA, Vande Velde C (2011) TAR DNA-binding protein 43 (TDP-43) regulates stress granule dynamics via differential regulation of G3BP and TIA-1. Hum Mol Genet 20:1400–1410. https://doi.org/10.1093/hmg/ddr021 Altman T, Ionescu A, Ibraheem A, Priesmann D, Gradus-Pery T, Farberov L, Alexandra G, Shelestovich N, Dafinca R, Shomron N et al (2021) Axonal TDP-43 condensates drive neuromuscular junction disruption through inhibition of local synthesis of nuclear encoded mitochondrial proteins. Nat Commun 12:6914. https://doi.org/10.1038/s41467-021-27221-8 Coyne AN, Lorenzini I, Chou CC, Torvund M, Rogers RS, Starr A, Zaepfel BL, Levy J, Johannesmeyer J, Schwartz JC et al (2017) Post-transcriptional inhibition of Hsc70-4/HSPA8 expression leads to synaptic vesicle cycling defects in multiple models of ALS. Cell Rep 21:110–125. https://doi.org/10.1016/j.celrep.2017.09.028 Lehmkuhl EM, Loganathan S, Alsop E, Blythe AD, Kovalik T, Mortimore NP, Barrameda D, Kueth C, Eck RJ, Siddegowda BB et al (2021) TDP-43 proteinopathy alters the ribosome association of multiple mRNAs including the glypican Dally-like protein (Dlp)/GPC6. Acta Neuropathol Commun 9:52. https://doi.org/10.1186/s40478-021-01148-z Ramaswami M, Taylor JP, Parker R (2013) Altered ribostasis: RNA-protein granules in degenerative disorders. Cell 154:727–736. https://doi.org/10.1016/j.cell.2013.07.038 Walker AK, Spiller KJ, Ge G, Zheng A, Xu Y, Zhou M, Tripathy K, Kwong LK, Trojanowski JQ, Lee VMY (2015) Functional recovery in new mouse models of ALS/FTLD after clearance of pathological cytoplasmic TDP-43. Acta Neuropathol 130:643–660. https://doi.org/10.1007/s00401-015-1460-x Erwin DH (2015) Early metazoan life: divergence, environment and ecology. Philos Trans R Soc Lond B Biol Sci. https://doi.org/10.1098/rstb.2015.0036 Ayala YM, Pantano S, D’Ambrogio A, Buratti E, Brindisi A, Marchetti C, Romano M, Baralle FE (2005) Human, Drosophila, and C.elegans TDP43: nucleic acid binding properties and splicing regulatory function. J Mol Biol 348:575–588. https://doi.org/10.1016/j.jmb.2005.02.038 Estes PS, Boehringer A, Zwick R, Tang JE, Grigsby B, Zarnescu DC (2011) Wild-type and A315T mutant TDP-43 exert differential neurotoxicity in a Drosophila model of ALS. Hum Mol Genet 20:2308–2321. https://doi.org/10.1093/hmg/ddr124 Bier E (2005) Drosophila, the golden bug, emerges as a tool for human genetics. Nat Rev Genet 6:9–23. https://doi.org/10.1038/nrg1503 Bridi JC, Ludlow ZN, Kottler B, Hartmann B, Vanden Broeck L, Dearlove J, Goker M, Strausfeld NJ, Callaerts P, Hirth F (2020) Ancestral regulatory mechanisms specify conserved midbrain circuitry in arthropods and vertebrates. Proc Natl Acad Sci U S A 117:19544–19555. https://doi.org/10.1073/pnas.1918797117 Strausfeld NJ, Hirth F (2013) Deep homology of arthropod central complex and vertebrate basal ganglia. Science 340:157–161. https://doi.org/10.1126/science.1231828 Muqit MM, Feany MB (2002) Modelling neurodegenerative diseases in Drosophila: a fruitful approach? Nat Rev Neurosci 3:237–243. https://doi.org/10.1038/nrn751 Heisenberg M (2003) Mushroom body memoir: from maps to models. Nat Rev Neurosci 4:266–275. https://doi.org/10.1038/nrn1074 Isabel G, Pascual A, Preat T (2004) Exclusive consolidated memory phases in Drosophila. Science 304:1024–1027. https://doi.org/10.1126/science.1094932 Shaw PJ, Cirelli C, Greenspan RJ, Tononi G (2000) Correlates of sleep and waking in Drosophila melanogaster. Science 287:1834–1837. https://doi.org/10.1126/science.287.5459.1834 Baier A, Wittek B, Brembs B (2002) Drosophila as a new model organism for the neurobiology of aggression? J Exp Biol 205:1233–1240. https://doi.org/10.1242/jeb.205.9.1233 Kamyshev NG, Smirnova GP, Kamysheva EA, Nikiforov ON, Parafenyuk IV, Ponomarenko VV (2002) Plasticity of social behavior in Drosophila. Neurosci Behav Physiol 32:401–408. https://doi.org/10.1023/a:1015832328023 Bellen HJ (1998) The fruit fly: a model organism to study the genetics of alcohol abuse and addiction? Cell 93:909–912. https://doi.org/10.1016/s0092-8674(00)81195-2 Li Y, Ray P, Rao EJ, Shi C, Guo W, Chen X, Woodruff EA 3rd, Fushimi K, Wu JY (2010) A Drosophila model for TDP-43 proteinopathy. Proc Natl Acad Sci U S A 107:3169–3174. https://doi.org/10.1073/pnas.0913602107 Romano M, Feiguin F, Buratti E (2012) Drosophila Answers to TDP-43 Proteinopathies. J Amino Acids 2012:356081. https://doi.org/10.1155/2012/356081 Coyne AN, Siddegowda BB, Estes PS, Johannesmeyer J, Kovalik T, Daniel SG, Pearson A, Bowser R, Zarnescu DC (2014) Futsch/MAP1B mRNA is a translational target of TDP-43 and is neuroprotective in a Drosophila model of amyotrophic lateral sclerosis. J Neurosci 34:15962–15974. https://doi.org/10.1523/JNEUROSCI.2526-14.2014 Azpurua J, El-Karim EG, Tranquille M, Dubnau J (2021) A behavioral screen for mediators of age-dependent TDP-43 neurodegeneration identifies SF2/SRSF1 among a group of potent suppressors in both neurons and glia. PLoS Genet 17:e1009882. https://doi.org/10.1371/journal.pgen.1009882 Coyne AN, Yamada SB, Siddegowda BB, Estes PS, Zaepfel BL, Johannesmeyer JS, Lockwood DB, Pham LT, Hart MP, Cassel JA et al (2015) Fragile X protein mitigates TDP-43 toxicity by remodeling RNA granules and restoring translation. Hum Mol Genet 24:6886–6898. https://doi.org/10.1093/hmg/ddv389 Sreedharan J, Neukomm LJ, Brown RH Jr, Freeman MR (2015) Age-dependent TDP-43-mediated motor neuron degeneration requires GSK3, hat-trick, and xmas-2. Curr Biol 25:2130–2136. https://doi.org/10.1016/j.cub.2015.06.045 Zhan L, Hanson KA, Kim SH, Tare A, Tibbetts RS (2013) Identification of genetic modifiers of TDP-43 neurotoxicity in Drosophila. PLoS ONE 8:e57214. https://doi.org/10.1371/journal.pone.0057214 Loganathan S, Wilson BA, Carey SB, Manzo E, Joardar A, Ugur B, Zarnescu DC (2022) TDP-43 proteinopathy causes broad metabolic alterations including TCA cycle intermediates and dopamine levels in drosophila models of ALS. Metabolites. https://doi.org/10.3390/metabo12020101 Manzo E, Lorenzini I, Barrameda D, O’Conner AG, Barrows JM, Starr A, Kovalik T, Rabichow BE, Lehmkuhl EM, Shreiner DD et al (2019) Glycolysis upregulation is neuroprotective as a compensatory mechanism in ALS. Elife. https://doi.org/10.7554/eLife.45114 de Belle JS, Heisenberg M (1994) Associative odor learning in Drosophila abolished by chemical ablation of mushroom bodies. Science 263:692–695. https://doi.org/10.1126/science.8303280 Liu L, Wolf R, Ernst R, Heisenberg M (1999) Context generalization in Drosophila visual learning requires the mushroom bodies. Nature 400:753–756. https://doi.org/10.1038/23456 Vogt K, Schnaitmann C, Dylla KV, Knapek S, Aso Y, Rubin GM, Tanimoto H (2014) Shared mushroom body circuits underlie visual and olfactory memories in Drosophila. Elife 3:e02395. https://doi.org/10.7554/eLife.02395 Ostrowski D, Kahsai L, Kramer EF, Knutson P, Zars T (2015) Place memory retention in Drosophila. Neurobiol Learn Mem 123:217–224. https://doi.org/10.1016/j.nlm.2015.06.015 Driscoll M, Buchert SN, Coleman V, McLaughlin M, Nguyen A, Sitaraman D (2021) Compartment specific regulation of sleep by mushroom body requires GABA and dopaminergic signaling. Sci Rep 11:20067. https://doi.org/10.1038/s41598-021-99531-2 Joiner WJ, Crocker A, White BH, Sehgal A (2006) Sleep in Drosophila is regulated by adult mushroom bodies. Nature 441:757–760. https://doi.org/10.1038/nature04811 Tsao CH, Chen CC, Lin CH, Yang HY, Lin S (2018) Drosophila mushroom bodies integrate hunger and satiety signals to control innate food-seeking behavior. Elife. https://doi.org/10.7554/eLife.35264 Sun Y, Qiu R, Li X, Cheng Y, Gao S, Kong F, Liu L, Zhu Y (2020) Social attraction in Drosophila is regulated by the mushroom body and serotonergic system. Nat Commun 11:5350. https://doi.org/10.1038/s41467-020-19102-3 Zhang K, Guo JZ, Peng Y, Xi W, Guo A (2007) Dopamine-mushroom body circuit regulates saliency-based decision-making in Drosophila. Science 316:1901–1904. https://doi.org/10.1126/science.1137357 Zwarts L, Vanden Broeck L, Cappuyns E, Ayroles JF, Magwire MM, Vulsteke V, Clements J, Mackay TF, Callaerts P (2015) The genetic basis of natural variation in mushroom body size in Drosophila melanogaster. Nat Commun 6:10115. https://doi.org/10.1038/ncomms10115 Wolff GH, Strausfeld NJ (2016) Genealogical correspondence of a forebrain centre implies an executive brain in the protostome-deuterostome bilaterian ancestor. Philos Trans R Soc Lond B Biol Sci 371:20150055. https://doi.org/10.1098/rstb.2015.0055 Mariano V, Achsel T, Bagni C, Kanellopoulos AK (2020) Modelling learning and memory in drosophila to understand intellectual disabilities. Neuroscience 445:12–30. https://doi.org/10.1016/j.neuroscience.2020.07.034 Chakraborty R, Vepuri V, Mhatre SD, Paddock BE, Miller S, Michelson SJ, Delvadia R, Desai A, Vinokur M, Melicharek DJ et al (2011) Characterization of a Drosophila Alzheimer’s disease model: pharmacological rescue of cognitive defects. PLoS ONE 6:e20799. https://doi.org/10.1371/journal.pone.0020799 Team RC (2021) A language and environment for statistical computing. R Foundation for Statistical Computing, City Team R (2022) RStudio: Integrated Development Environment for R. PBC, City Wickham H, Averick M, Bryan J, Chang W, McGowan L, François R, Grolemund G, Hayes A, Henry L, Hester J et al (2019) Welcome to the Tidyverse. J Open Sour Softw. https://doi.org/10.21105/joss.01686 Kassambara A (2020) ggpubr: 'ggplot2' Based Publication Ready Plots. City Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate a practical and powerful approach to multiple testing. J Roy Stat Soc Ser B (Methodol) 57:289–300 Aso Y (2021) Split-GAL4 Mushroom Body Driver Line City Stewart BA, Atwood HL, Renger JJ, Wang J, Wu CF (1994) Improved stability of Drosophila larval neuromuscular preparations in haemolymph-like physiological solutions. J Comp Physiol A 175:179–191. https://doi.org/10.1007/BF00215114 Lewis SA, Negelspach DC, Kaladchibachi S, Cowen SL, Fernandez F (2017) Spontaneous alternation: a potential gateway to spatial working memory in Drosophila. Neurobiol Learn Mem 142:230–235. https://doi.org/10.1016/j.nlm.2017.05.013 Bates D, Mächler M, Bolker B, Walker S (2015) Fitting linear mixed-effects models usinglme4. J Stat Softw. https://doi.org/10.18637/jss.v067.i01 Chiu JC, Low KH, Pike DH, Yildirim E, Edery I (2010) Assaying locomotor activity to study circadian rhythms and sleep parameters in Drosophila. J Vis Exp. https://doi.org/10.3791/2157 Cichewicz K, Hirsh J (2018) ShinyR-DAM: a program analyzing Drosophila activity, sleep and circadian rhythms. Commun Biol 1:25. https://doi.org/10.1038/s42003-018-0031-9 Therneau TM (2021) A Package for Survival Analysis in R_. R package version 3.2-13. City Kassambara A, Kosinski M, Biecek P (2021) survminer: Drawing Survival Curves using 'ggplot2'. R package version 0.4.9 Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, Batut P, Chaisson M, Gingeras TR (2013) STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29:15–21. https://doi.org/10.1093/bioinformatics/bts635 Liao Y, Smyth GK, Shi W (2014) featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics 30:923–930. https://doi.org/10.1093/bioinformatics/btt656 Love MI, Huber W, Anders S (2014) Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 15:550. https://doi.org/10.1186/s13059-014-0550-8 Dennis G Jr, Sherman BT, Hosack DA, Yang J, Gao W, Lane HC, Lempicki RA (2003) DAVID: database for annotation, visualization, and integrated discovery. Genome Biol 4:P3 Sherman BT, Hao M, Qiu J, Jiao X, Baseler MW, Lane HC, Imamichi T, Chang W (2022) DAVID: a web server for functional enrichment analysis and functional annotation of gene lists (2021 update). Nucl Acids Res 50:W216-221. https://doi.org/10.1093/nar/gkac194 Gittings LM, Alsop EB, Antone J, Singer M, Whitsett TG, Sattler R, Van Keuren-Jensen K (2023) Cryptic exon detection and transcriptomic changes revealed in single-nuclei RNA sequencing of C9ORF72 patients spanning the ALS-FTD spectrum. Acta Neuropathol. https://doi.org/10.1007/s00401-023-02599-5 Hu Y, Comjean A, Rodiger J, Liu Y, Gao Y, Chung V, Zirin J, Perrimon N, Mohr SE (2021) FlyRNAi.org-the database of the Drosophila RNAi screening center and transgenic RNAi project: 2021 update. Nucl Acids Res 49:D908–D915. https://doi.org/10.1093/nar/gkaa936 Crittenden (1998) Tripartite Mushroom Body Architecture Revealed by Antigenic Markers Aso Y, Hattori D, Yu Y, Johnston RM, Iyer NA, Ngo TT, Dionne H, Abbott LF, Axel R, Tanimoto H et al (2014) The neuronal architecture of the mushroom body provides a logic for associative learning. Elife 3:e04577. https://doi.org/10.7554/eLife.04577 Estes PS, Daniel SG, McCallum AP, Boehringer AV, Sukhina AS, Zwick RA, Zarnescu DC (2013) Motor neurons and glia exhibit specific individualized responses to TDP-43 expression in a Drosophila model of amyotrophic lateral sclerosis. Dis Model Mech 6:721–733. https://doi.org/10.1242/dmm.010710 Kunz T, Kraft KF, Technau GM, Urbach R (2012) Origin of Drosophila mushroom body neuroblasts and generation of divergent embryonic lineages. Development 139:2510–2522. https://doi.org/10.1242/dev.077883 Lee T, Lee A, Luo L (1999) Development of the Drosophila mushroom bodies: sequential generation of three distinct types of neurons from a neuroblast. Development 126:4065–4076. https://doi.org/10.1242/dev.126.18.4065 Poos JM, Jiskoot LC, Papma JM, van Swieten JC, van den Berg E (2018) Meta-analytic review of memory impairment in behavioral variant frontotemporal dementia. J Int Neuropsychol Soc 24:593–605. https://doi.org/10.1017/S1355617718000115 Stopford CL, Thompson JC, Neary D, Richardson AM, Snowden JS (2012) Working memory, attention, and executive function in Alzheimer’s disease and frontotemporal dementia. Cortex 48:429–446. https://doi.org/10.1016/j.cortex.2010.12.002 Sani TP, Bond RL, Marshall CR, Hardy CJD, Russell LL, Moore KM, Slattery CF, Paterson RW, Woollacott IOC, Wendi IP et al (2019) Sleep symptoms in syndromes of frontotemporal dementia and Alzheimer’s disease: a proof-of-principle behavioural study. eNeurol Sci 17:100212. https://doi.org/10.1016/j.ensci.2019.100212 Bonakis A, Economou NT, Paparrigopoulos T, Bonanni E, Maestri M, Carnicelli L, Di Coscio E, Ktonas P, Vagiakis E, Theodoropoulos P et al (2014) Sleep in frontotemporal dementia is equally or possibly more disrupted, and at an earlier stage, when compared to sleep in Alzheimer’s disease. J Alzheimers Dis 38:85–91. https://doi.org/10.3233/JAD-122014 Li J, Vitiello MV, Gooneratne NS (2018) Sleep in normal aging. Sleep Med Clin 13:1–11. https://doi.org/10.1016/j.jsmc.2017.09.001 Kansal K, Mareddy M, Sloane KL, Minc AA, Rabins PV, McGready JB, Onyike CU (2016) Survival in frontotemporal dementia phenotypes: a meta-analysis. Dement Geriatr Cogn Disord 41:109–122. https://doi.org/10.1159/000443205 Loi SM, Tsoukra P, Chen Z, Wibawa P, Eratne D, Kelso W, Walterfang M, Velakoulis D (2021) Risk factors to mortality and causes of death in frontotemporal dementia: an Australian perspective. Int J Geriatr Psychiatry. https://doi.org/10.1002/gps.5668 Liao W, Luo H, Ruan Y, Mai Y, Liu C, Chen J, Yang S, Xuan A, Liu J (2022) Identification of candidate genes associated with clinical onset of Alzheimer’s disease. Front Neurosci 16:1060111. https://doi.org/10.3389/fnins.2022.1060111 Lien WY, Chen YT, Li YJ, Wu JK, Huang KL, Lin JR, Lin SC, Hou CC, Wang HD, Wu CL et al (2020) Lifespan regulation in alpha/beta posterior neurons of the fly mushroom bodies by Rab27. Aging Cell 19:e13179. https://doi.org/10.1111/acel.13179 Xiao S, Sanelli T, Dib S, Sheps D, Findlater J, Bilbao J, Keith J, Zinman L, Rogaeva E, Robertson J (2011) RNA targets of TDP-43 identified by UV-CLIP are deregulated in ALS. Mol Cell Neurosci 47:167–180. https://doi.org/10.1016/j.mcn.2011.02.013 Susnjar U, Skrabar N, Brown AL, Abbassi Y, Phatnani H, Consortium NA, Cortese A, Cereda C, Bugiardini E, Cardani R et al (2022) Cell environment shapes TDP-43 function with implications in neuronal and muscle disease. Commun Biol 5:314. https://doi.org/10.1038/s42003-022-03253-8 Yan D, Wu Y, Feng Y, Lin SC, Lin X (2009) The core protein of glypican Dally-like determines its biphasic activity in wingless morphogen signaling. Dev Cell 17:470–481. https://doi.org/10.1016/j.devcel.2009.09.001 Waghmare I, Wang X, Page-McCaw A (2020) Dally-like protein sequesters multiple Wnt ligands in the Drosophila germarium. Dev Biol 464:88–102. https://doi.org/10.1016/j.ydbio.2020.05.004 Rawson JM, Dimitroff B, Johnson KG, Rawson JM, Ge X, Van Vactor D, Selleck SB (2005) The heparan sulfate proteoglycans Dally-like and Syndecan have distinct functions in axon guidance and visual-system assembly in Drosophila. Curr Biol 15:833–838. https://doi.org/10.1016/j.cub.2005.03.039 Santiago JA, Bottero V, Potashkin JA (2020) Transcriptomic and network analysis identifies shared and unique pathways across dementia spectrum disorders. Int J Mol Sci. https://doi.org/10.3390/ijms21062050 Kunkle BW, Schmidt M, Klein HU, Naj AC, Hamilton-Nelson KL, Larson EB, Evans DA, De Jager PL, Crane PK, Buxbaum JD et al (2021) Novel Alzheimer disease risk loci and pathways in African American Individuals using the African genome resources panel: a meta-analysis. JAMA Neurol 78:102–113. https://doi.org/10.1001/jamaneurol.2020.3536 Sherva R, Zhang R, Sahelijo N, Jun G, Anglin T, Chanfreau C, Cho K, Fonda JR, Gaziano JM, Harrington KM et al (2023) African ancestry GWAS of dementia in a large military cohort identifies significant risk loci. Mol Psychiatry 28:1293–1302. https://doi.org/10.1038/s41380-022-01890-3 Panitch R, Hu J, Xia W, Bennett DA, Stein TD, Farrer LA, Jun GR (2022) Blood and brain transcriptome analysis reveals APOE genotype-mediated and immune-related pathways involved in Alzheimer disease. Alzheimers Res Ther 14:30. https://doi.org/10.1186/s13195-022-00975-z Martin S, Chamberlin A, Shinde DN, Hempel M, Strom TM, Schreiber A, Johannsen J, Ousager LB, Larsen MJ, Hansen LK et al (2017) De novo variants in GRIA4 lead to intellectual disability with or without seizures and gait abnormalities. Am J Hum Genet 101:1013–1020. https://doi.org/10.1016/j.ajhg.2017.11.004 Chen Y, Liu XH, Wu JJ, Ren HM, Wang J, Ding ZT, Jiang YP (2016) Proteomic analysis of cerebrospinal fluid in amyotrophic lateral sclerosis. Exp Ther Med 11:2095–2106. https://doi.org/10.3892/etm.2016.3210 Zhang Q, Ma C, Gearing M, Wang PG, Chin LS, Li L (2018) Integrated proteomics and network analysis identifies protein hubs and network alterations in Alzheimer’s disease. Acta Neuropathol Commun 6:19. https://doi.org/10.1186/s40478-018-0524-2 Maia da Silva MN, Porto FHG, Lopes PMG, de Castro S, Prado C, Frota NAF, Alves CHL, Alves GS (2021) Frontotemporal dementia and late-onset bipolar disorder: the many directions of a busy road. Front Psychiatry 12:768722. https://doi.org/10.3389/fpsyt.2021.768722 Happ HC, Sadleir LG, Zemel M, de Valles-Ibanez G, Hildebrand MS, McConkie-Rosell A, McDonald M, May H, Sands T, Aggarwal V et al (2023) Neurodevelopmental and epilepsy phenotypes in individuals with missense variants in the voltage-sensing and pore domains of KCNH5. Neurology 100:e603–e615. https://doi.org/10.1212/WNL.0000000000201492 Boscia F, Elkjaer ML, Illes Z, Kukley M (2021) Altered expression of ion channels in white matter lesions of progressive multiple sclerosis: what do we know about their function? Front Cell Neurosci 15:685703. https://doi.org/10.3389/fncel.2021.685703 Mori H, Yoshino Y, Iga JI, Ochi S, Funahashi Y, Yamazaki K, Kumon H, Ozaki Y, Ueno SI (2023) Aberrant expression of GABA-related genes in the hippocampus of 3xTg-AD model mice from the early to end stages of Alzheimer’s disease. J Alzheimers Dis 94:177–188. https://doi.org/10.3233/JAD-230078 Niewiadomska-Cimicka A, Krzyzosiak A, Ye T, Podlesny-Drabiniok A, Dembele D, Dolle P, Krezel W (2017) Genome-wide analysis of RARbeta transcriptional targets in mouse striatum links retinoic acid signaling with Huntington’s disease and other neurodegenerative disorders. Mol Neurobiol 54:3859–3878. https://doi.org/10.1007/s12035-016-0010-4 Canchi S, Raao B, Masliah D, Rosenthal SB, Sasik R, Fisch KM, De Jager PL, Bennett DA, Rissman RA (2019) Integrating gene and protein expression reveals perturbed functional networks in Alzheimer’s disease. Cell Rep 28(1103–1116):e1104. https://doi.org/10.1016/j.celrep.2019.06.073 Castillo E, Leon J, Mazzei G, Abolhassani N, Haruyama N, Saito T, Saido T, Hokama M, Iwaki T, Ohara T et al (2017) Comparative profiling of cortical gene expression in Alzheimer’s disease patients and mouse models demonstrates a link between amyloidosis and neuroinflammation. Sci Rep 7:17762. https://doi.org/10.1038/s41598-017-17999-3 Castanho I, Murray TK, Hannon E, Jeffries A, Walker E, Laing E, Baulf H, Harvey J, Bradshaw L, Randall A et al (2020) Transcriptional Signatures of Tau and Amyloid Neuropathology. Cell Rep 30(2040–2054):e2045. https://doi.org/10.1016/j.celrep.2020.01.063 Bereczki E, Branca RM, Francis PT, Pereira JB, Baek JH, Hortobagyi T, Winblad B, Ballard C, Lehtio J, Aarsland D (2018) Synaptic markers of cognitive decline in neurodegenerative diseases: a proteomic approach. Brain 141:582–595. https://doi.org/10.1093/brain/awx352 Hill MA, Gammie SC (2022) Alzheimer’s disease large-scale gene expression portrait identifies exercise as the top theoretical treatment. Sci Rep 12:17189. https://doi.org/10.1038/s41598-022-22179-z Kuo HY, Chen SY, Huang RC, Takahashi H, Lee YH, Pang HY, Wu CH, Graybiel AM, Liu FC (2023) Speech- and language-linked FOXP2 mutation targets protein motors in striatal neurons. Brain. https://doi.org/10.1093/brain/awad090 Pennington C, Hodges JR, Hornberger M (2011) Neural correlates of episodic memory in behavioral variant frontotemporal dementia. J Alzheimers Dis 24:261–268. https://doi.org/10.3233/JAD-2011-101668 Mackenzie IRA, Rademakers R, Neumann M (2010) TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia. Lancet Neurol 9:995–1007. https://doi.org/10.1016/s1474-4422(10)70195-2 Feiguin F, Godena VK, Romano G, D’Ambrogio A, Klima R, Baralle FE (2009) Depletion of TDP-43 affects Drosophila motoneurons terminal synapsis and locomotive behavior. FEBS Lett 583:1586–1592. https://doi.org/10.1016/j.febslet.2009.04.019 Lu Y, Ferris J, Gao FB (2009) Frontotemporal dementia and amyotrophic lateral sclerosis-associated disease protein TDP-43 promotes dendritic branching. Mol Brain 2:30. https://doi.org/10.1186/1756-6606-2-30 Elden AC, Kim HJ, Hart MP, Chen-Plotkin AS, Johnson BS, Fang X, Armakola M, Geser F, Greene R, Lu MM et al (2010) Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature 466:1069–1075. https://doi.org/10.1038/nature09320 Aso Y, Grubel K, Busch S, Friedrich AB, Siwanowicz I, Tanimoto H (2009) The mushroom body of adult Drosophila characterized by GAL4 drivers. J Neurogenet 23:156–172. https://doi.org/10.1080/01677060802471718 Morante J, Desplan C (2008) The color-vision circuit in the medulla of Drosophila. Curr Biol 18:553–565. https://doi.org/10.1016/j.cub.2008.02.075 Enell LE, Kapan N, Soderberg JA, Kahsai L, Nassel DR (2010) Insulin signaling, lifespan and stress resistance are modulated by metabotropic GABA receptors on insulin producing cells in the brain of Drosophila. PLoS ONE 5:e15780. https://doi.org/10.1371/journal.pone.0015780 Hampel S, Chung P, McKellar CE, Hall D, Looger LL, Simpson JH (2011) Drosophila Brainbow: a recombinase-based fluorescence labeling technique to subdivide neural expression patterns. Nat Methods 8:253–259. https://doi.org/10.1038/nmeth.1566 Ash PE, Zhang YJ, Roberts CM, Saldi T, Hutter H, Buratti E, Petrucelli L, Link CD (2010) Neurotoxic effects of TDP-43 overexpression in C. elegans. Hum Mol Genet 19:3206–3218. https://doi.org/10.1093/hmg/ddq230 Park JH, Chung CG, Park SS, Lee D, Kim KM, Jeong Y, Kim ES, Cho JH, Jeon Y-M, Shen CKJ et al (2020) Cytosolic calcium regulates cytoplasmic accumulation of TDP-43 through Calpain-A and Importin α3. Elife 9:e60132. https://doi.org/10.7554/eLife.60132 Ito K, Awano W, Suzuki K, Hiromi Y, Yamamoto D (1997) The Drosophila mushroom body is a quadruple structure of clonal units each of which contains a virtually identical set of neurones and glial cells. Development 124:761–771. https://doi.org/10.1242/dev.124.4.761 Yu HH, Lee T (2007) Neuronal temporal identity in post-embryonic Drosophila brain. Trends Neurosci 30:520–526. https://doi.org/10.1016/j.tins.2007.07.003 Nana AL, Sidhu M, Gaus SE, Hwang JL, Li L, Park Y, Kim EJ, Pasquini L, Allen IE, Rankin KP et al (2019) Neurons selectively targeted in frontotemporal dementia reveal early stage TDP-43 pathobiology. Acta Neuropathol 137:27–46. https://doi.org/10.1007/s00401-018-1942-8 Seeley WW (2008) Selective functional, regional, and neuronal vulnerability in frontotemporal dementia. Curr Opin Neurol 21:701–707. https://doi.org/10.1097/WCO.0b013e3283168e2d Vatsavayai SC, Yoon SJ, Gardner RC, Gendron TF, Vargas JN, Trujillo A, Pribadi M, Phillips JJ, Gaus SE, Hixson JD et al (2016) Timing and significance of pathological features in C9orf72 expansion-associated frontotemporal dementia. Brain 139:3202–3216. https://doi.org/10.1093/brain/aww250 Perry DC, Brown JA, Possin KL, Datta S, Trujillo A, Radke A, Karydas A, Kornak J, Sias AC, Rabinovici GD et al (2017) Clinicopathological correlations in behavioural variant frontotemporal dementia. Brain 140:3329–3345. https://doi.org/10.1093/brain/awx254 Rascovsky K, Hodges JR, Knopman D, Mendez MF, Kramer JH, Neuhaus J, van Swieten JC, Seelaar H, Dopper EG, Onyike CU et al (2011) Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain 134:2456–2477. https://doi.org/10.1093/brain/awr179 Graham A, Davies R, Xuereb J, Halliday G, Kril J, Creasey H, Graham K, Hodges J (2005) Pathologically proven frontotemporal dementia presenting with severe amnesia. Brain 128:597–605. https://doi.org/10.1093/brain/awh348 Hornberger M, Piguet O (2012) Episodic memory in frontotemporal dementia: a critical review. Brain 135:678–692. https://doi.org/10.1093/brain/aws011 McCarter SJ, St Louis EK, Boeve BF (2016) Sleep disturbances in frontotemporal dementia. Curr Neurol Neurosci Rep 16:85. https://doi.org/10.1007/s11910-016-0680-3 Murphy SL, Kochanek KD, Xu J, Aria E (2021) Mortality in the United States, 2020. NCHS Data Brief. U.S. Department of Health and Human Services, City, p 8 Yamazaki D, Horiuchi J, Nakagami Y, Nagano S, Tamura T, Saitoe M (2007) The Drosophila DCO mutation suppresses age-related memory impairment without affecting lifespan. Nat Neurosci 10:478–484. https://doi.org/10.1038/nn1863 Mershin A, Pavlopoulos E, Fitch O, Braden BC, Nanopoulos DV, Skoulakis EM (2004) Learning and memory deficits upon TAU accumulation in Drosophila mushroom body neurons. Learn Mem 11:277–287. https://doi.org/10.1101/lm.70804 Bjork RT, Mortimore NP, Loganathan S, Zarnescu DC (2022) Dysregulation of translation in TDP-43 proteinopathies: deficits in the RNA supply chain and local protein production. Front Neurosci 16:840357. https://doi.org/10.3389/fnins.2022.840357 Langellotti S, Romano G, Feiguin F, Baralle FE, Romano M (2018) RhoGAPp190: a potential player in tbph-mediated neurodegeneration in Drosophila. PLoS ONE 13:e0195845. https://doi.org/10.1371/journal.pone.0195845 Harbison ST, Serrano Negron YL, Hansen NF, Lobell AS (2017) Selection for long and short sleep duration in Drosophila melanogaster reveals the complex genetic network underlying natural variation in sleep. PLoS Genet 13:e1007098. https://doi.org/10.1371/journal.pgen.1007098 Murley AG, Rowe JB (2018) Neurotransmitter deficits from frontotemporal lobar degeneration. Brain 141:1263–1285. https://doi.org/10.1093/brain/awx327 Chen Y, Guan Y, Zhang Z, Liu H, Wang S, Yu L, Wu X, Wang X (2013) Wnt signaling pathway is involved in the pathogenesis of amyotrophic lateral sclerosis in adult transgenic mice. Neurol Res 34:390–399. https://doi.org/10.1179/1743132812y.0000000027 Gonzalez-Fernandez C, Gonzalez P, Andres-Benito P, Ferrer I, Rodriguez FJ (2019) Wnt signaling alterations in the human spinal cord of amyotrophic lateral sclerosis cases: spotlight on Fz2 and Wnt5a. Mol Neurobiol 56:6777–6791. https://doi.org/10.1007/s12035-019-1547-9 Wexler EM, Rosen E, Lu D, Osborn GE, Martin E, Raybould H, Geschwind DH (2011) Genome-wide analysis of a Wnt1-regulated transcriptional network implicates neurodegenerative pathways. Sci Signal 4:ra65. https://doi.org/10.1126/scisignal.2002282 Area-Gomez E, Guardia-Laguarta C, Schon EA, Przedborski S (2019) Mitochondria, OxPhos, and neurodegeneration: cells are not just running out of gas. J Clin Invest 129:34–45. https://doi.org/10.1172/JCI120848