McMillan M*, Gomez N*, Hsieh C, Bekier M, Li X, Miguez R, Tank EM, Barmada SJ. RNA methylation influences TDP43 binding and disease pathogenesis in models of amyotrophic lateral sclerosis and frontotemporal dementia. Molecular Cell. 2023 Jan 4;S1097-2765(22)01176-5. doi: 10.1016/j.molcel.2022.12.019.
Malik AM, Wu JJ, Gillies CA, Doctrove QA, Li X, Huang H, Tank EM, Shakkottai VG, Barmada SJ. Neuronal activity regulates Matrin 3 levels and function in a calcium-dependent manner through calpain cleavage and calmodulin binding. Proceedings of the National Academy of Sciences. 2023 April 3 120 (15) e2206217120
Krishnan G, Raitcheva D, Bartlett D, Prudencio M, McKenna-Yasek D, Douthwright C, Oskarsson B, Fiorelli R, King O, Barmada SJ, Miller T, Bowser R, Watts J, Petrucelli L, Brown R, Kankel M, and Gao F-B. Poly(GR) and Poly(GA) in Cerebrospinal Fluid as Potential Biomarkers for C9ORF72-ALS/FTD. Nature Communications. 2022. May 19;13(1):2799. doi: 10.1038/s41467-022-30387-4.
Chua C, Bedi K, Paulsen MT, Ljungman M, Tank EM, Kim ES, Colón-Mercado JM, Ward ME, Weisman LS, Santoro N, Barmada SJ. ​Myotubularin-related phosphatase 5 is a critical determinant of autophagy in neurons. Current Biology. 2022. Jun 20;32(12):2581-2595.e6​
François-Moutal L, Scott DD,  Dissanayake K, May DG, Carlson JM, Ambrose AJ, Zerio CJ, Barbieri E, Moutal A, Chapman E, Roux KJ, Shorter J, Khanna R, Barmada SJ, McGurk L, Khanna M. Heat shock protein Grp78/BiP/HspA5 binds directly to TDP-43 and mitigates toxicity associated with disease pathology. Scientific Reports. 2022. May 17;12(1):8140.
Safren N, Tank EM, Malik M, Chua J, Santoro N, Barmada SJ. Development of a specific live-cell assay for native autophagic flux. Journal of Biochemistry. 2021 Sep;297(3):101003. doi: 10.1016/j.jbc.2021.101003.
Sidibé H, Khalfallah Y, Xiao S, Gómez NB, Tank EMH, Di Tomasso G, Bareke E, Aulas A, McKeever P, Melamed Z, Destroimaisons L, Deshaies J-E, Zinman L, Parker JA, Legault P, Tétreault M, Barmada SJ, Robertson J, and Vande Velde C. Transcripts encoding the central stress granule protein G3BP1 are stabilized by TDP-43: potential relevance to ALS/FTD. Brain 2021 Dec 16;144(11):3461-3476.
 doi: 10.1093/brain/awab217
Maimon R*, Ankol L*, Altman T, Ionescu A, Weissova R, Gradus TP, Ostrovsky M, Tank EM, Alexandra G, Shelestovich N, Opatowsky Y, Dori A, Barmada SJ, Balastik M, Perlson E. CRMP4-Dynein Complex Formation Mediate Retrograde Death Signal in ALS. European Molecular Biology (EMBO) Journal 2021 Sep 1;40(17):e107586.  doi: 10.15252/embj.2020107586
Chua J, de Calbiac H, Kabashi E, Barmada SJ. Autophagy and ALS: Mechanistic Insights and Therapeutic Implications. Autophagy 2021 May 31;1-29. doi: 10.1080/15548627.2021.1926656
Safren N, Sharkey L, Barmada SJ. Neuronal puncta/aggregate formation by WT and mutant UBQLN2. Methods in Molecular Biology. 2023;2551:561-573. doi: 10.1007/978-1-0716-2597-2_34.
Moinuddin O, Khandwala NS, Young KZ, Sathrasala SK, Barmada SJ, Albin R, and Besirli CG. The Role of Optical Coherence Tomography in Identifying Retinal Biomarkers in FTD: A Review. Neurology: Clinical Practice. January 25, 2021, DOI: https://doi.org/10.1212/CPJ.0000000000001041
Malik A and Barmada SJ. Matrin 3 in neuromuscular disease: physiology and pathophysiology. Journal of Clinical Investigation Insight. ​2021 Jan 11; 6(1): e143948.
Mollasalehi N, Francois-Moutal L, Scott D, Tello J, Williams H, Mahoney B, Carlson J, Dong Y, Li X, Miranda V, Gokhale V, Wang W, Barmada SJ, Khanna M. An allosteric modulator of RNA binding targeting the N-terminal domain of TDP-43 yields neuroprotective properties. ACS Chemical Biology. 2020 Nov 20;15(11):2854-2859.
Gerson JE, Safren N, Fischer S, Patel R, Crowley EV, Welday JP, Windle AK, Barmada SJ, Paulson HL, Sharkey. Ubiquilin-2 differentially regulates polyglutamine disease proteins. Human Molecular Genetics 29(15):2596.
He F, Flores BN, Krans A, Frazer M, Natla S, Niraula S, Adefioye O, Barmada SJ, Todd PK. The carboxyl termini of RAN translated GGGGCC nucleotide repeat expansions modulate toxicity in models of ALS/FTD. Acta Neuropathologica Communications. 2020 Aug 4;8(1):122.
  • Dipeptide repeat proteins produced by repeat-associated non-AUG (RAN) translation ma contribute to neurodegeneration in ALS/FTD due to C9orf72 mutations. In manipulating sequences following the C9orf72 mutation itself, this work shows that C-terminal sequences outside of the repeat region may alter the behavior and toxicity of dipeptide repeat proteins in model systems
Malik AM, Barmada SJ. TDP-43 Nuclear Bodies: A NEAT response to stress? Molecular Cell. 2020 Aug 6;79(3):362-364.
  • In this commentary, we review the findings of Wang et al. in the same issue of Molecular Cell, who investigated stress-induced nuclear condensates of TDP-43. In the process, they uncovered a protective function for TDP-43 rich nuclear bodies, and described a unique scaffolding mechanism involving the non-coding RNA NEAT1. 
Rodriguez CM, Wright SE, Kearse MG, Haenfler J, Flores BN, Liu Y, Ifrim MF, Glineburg MR, Krans A, Paymaan JN, Sutton M, Bassell GJ, Parent JM, Rigo F, Barmada SJ, Todd PK. A native function for RAN translation and CGG repeats in regulating fragile X protein synthesis. Nature Neuroscience. 2020 23, 386–397.
  • This is the first demonstration of an endogenous function for microsattelite repeats and RAN translation, in regulating activity-dependent synthesis of FMRP. Furthermore, prevention of RAN translation from expanded CGG repeats prevented neurodegeneration in a model of fragile-X associated disease.
Weskamp K, Tank EM, Miguez R, McBride JP, Gómez NB, White M, Lin Z, Moreno Gonzalez C, Serio A, Sreedharan J, Barmada SJ. Shortened TDP43 isoforms upregulated by neuronal hyperactivity drive TDP43 pathology in ALS.  Journal of Clinical Investigation. 2020 Mar 2;130(3):1139-1155.
  • In this manuscript, we describe TDP43 splice variants lacking the C-terminus whose expression is regulated by neuronal hyperactivity, a conserved feature in ALS. These shortened (s) TDP43 variants are also enriched in spinal motor neurons, exported from the nucleus, inherently prone to aggregation, and co-localize with TDP43 pathology in patient samples, providing strong evidence for their contribution to disease mechanisms operating in ALS. 
Green KM, Sheth U, Flores BN, Wright SE, Sutter A, Kearse MG, Barmada SJ, Ivanova MI, Todd PK. High-throughput screening yields several small-molecule inhibitors of repeat-associated non-AUG translation. Journal of Biological Chemistry 2019 Oct 23. pii: jbc.RA119.009951.
  • Over 3000 compounds were screened for their ability to block repeat-associated non-AUG (RAN) translation, uncovering a diverse set of small molecules with potent activity against RAN translation. These findings provide proof-of-principle supporting the development of selective small-molecule RAN translation inhibitors that act across multiple disease-causing repeats.
Linsalata AE, He F, Malik AM, Glineburg MR, Green KM, Natla S, Flores BN, Krans A, Archbold HC, Fedak SJ, Barmada SJ, Todd PK. DDX3X and specific initiation factors modulate FMR1 repeat-associated non-AUG-initiated translation. EMBO Reports 2019 Sep;20(9):e47498.
  • These studies uncovered novel factors acting on repeat-associated non-AUG-initiated (RAN) translation, a process implicated in ALS, FTD and other conditions such as fragile X-associated tremor ataxia syndrome (FXTAS). Inhibiting the RNA helicase DDX3X blocked RAN translation and mitigated toxicity in multiple model systems, making it a potential therapeutic target in these disorders.
Flores BN, Malik A, Li X, Martinez Jose, Beg AA, and Barmada SJ. An Intramolecular Salt Bridge Linking TDP43's RNA Recognition Motifs Dictates RNA Binding, Protein Stability and TDP43-Dependent Neurodegeneration. Cell Reports 2019, 27:1133-1150. 
  • Here we uncover essential roles for an intramolecular salt bridge in TDP43 function and metabolism. Salt bridge interruption attenuates TDP43’s RNA binding affinity and specificity, destabilizes the protein, and prevents TDP43-mediated neurotoxicity arising from misprocessing of ribosomal and mitochondrial transcripts.
Weskamp K*, Safren N*, Miguez R, and Barmada SJ. ​Monitoring neuronal survival via longitudinal fluorescence microscopy. Journal of Visualized Experiments 2019 (143), e59036, doi:10.3791/59036
  • This manuscript and associated video provides a detailed explanation of longitudinal microscopy for the analysis of cellular survival.  
Sharkey LM*, Safren N*, Pithadia AS*, Gerson JE, Dulchavsky M, Fischer S, Patel R, Lantis G, Ashraf N, Kim JH, Meliki A, Minakawa EN, Barmada SJ#, Ivanova MI#, Paulson HL#. Mutant UBQLN2 promotes toxicity by modulating intrinsic self-assembly. Proceedings of the National Academy of Sciences of the United States of America 2018 Oct 30;115(44): E10495.
  • UBQLN2 mutations are responsible for X-linked ALS and FTD. In this collaborative work, we investigate how UBQLN2 mutations affect the intrinsic biophysical properties of UBQLN2 in vitro, and their impact on UBQLN2 behavior and toxicity in cultured cells, primary neurons and transgenic animals.  
Malik A, Miguez R, Li X, Ho YS, Feldman EL, and Barmada SJ. Matrin 3-dependent neurotoxicity is modified by nucleic acid binding and nucleocytoplasmic localization. eLife 2018;7:e35977.
  • Mutations in the gene encoding Matrin3 result in ALS, FTD and/or myopathy. Here, we establish a neuronal model of Matrin3-dependent disease, and take advantage of this system to identify the key domains and properties of Matrin3 that contribute to neuronal loss. 
Tank EM, Figueroa-Romero C, Hinder LM, Bedi K, Archbold HC, Li X, Weskamp K, Safren N, Paez-Colasante X, Pacut C, Thumma S, Paulsen MT, Guo K, Hur J, Ljungman M, Feldman EL, and Barmada SJ. Abnormal RNA stability in amyotrophic lateral sclerosis. Nature Communications 2018. 9:2845.
  • This is the first direct demonstration of abnormal RNA stability in ALS patient derived cells. In this manuscript, we find that instability of 2 key classes of transcripts are conserved features of ALS due to C9orf72 mutations, and that TDP43 deposition is sufficient to reproduce an almost identical pattern in control cells. These data implicate TDP43 as a fundamental driver of RNA instability in ALS.
Archbold HC, Jackson K, Arora A, Weskamp K, Tank EM, Li X, Miguez R, Dayton RD, Tamir S, Klein RL, and Barmada SJ. TDP43 nuclear export and neurodegeneration in models of amyotrophic lateral sclerosis and frontotemporal dementia. Scientific Reports 2018. Mar 15;8(1):4606
  • Cytoplasmic accumulation and nuclear clearing of TDP43 are conserved features of ALS and FTD, yet the mechanisms involved in TDP43 nuclear export remain unclear. Here, we show that several nuclear exporters are sufficient for nuclear TDP43 export, but no single exporter is necessary.
Weskamp K, and Barmada SJ. TDP43 and RNA instability in amyotrophic lateral sclerosis. Brain Research, 2018 Jan 29. pii: S0006-8993(18)30023-4.
  • An overview of how the integral RNA binding protein TDP43 contributes to abnormal RNA stability in ALS.
Al-Ramahi I, Panapakkam Giridharan SS, Chen YC, Patnaik S, Safren N, Hasegawa J, de Haro M, Wagner Gee AK, Titus SA, Jeong H, Clarke J, Krainc D, Zheng W, Irvine RF, Barmada S, Ferrer M, Southall N, Weisman LS, Botas J, Marugan JJ. Inhibition of PIP4Kγ ameliorates the pathological effects of mutant huntingtin protein. Elife. 2017 Dec 26;6. pii: e29123. 
  • Novel pharmacologic inhibitors of PIP4Kg, a component of the phosphoinositide signaling pathway, prevent toxicity from mutant huntingtiin by enhancing its degradation via autophagy.
Green KM, Glineburg MR, Kearse MG, Flores BN, Linsalata AE, Fedak SJ, Goldstrohm AC, Barmada SJ, Todd PK. RAN translation at C9orf72-associated repeat  expansions is selectively enhanced by the integrated stress response. Nat Commun. 2017 Dec 8;8(1):2005.
  • These investigations establish the molecular mechanism of repeat associated non-AUG (RAN) translation, and uncover a positive-feedback loop involving RAN translation and stress that culminates in cell death. 
Wang B, Zeng L, Merillat SA, Fischer S, Ochaba J, Thompson LM, Barmada SJ, Scaglione KM, Paulson HL. The ubiquitin conjugating enzyme Ube2W regulates solubility of the Huntington's disease protein, huntingtin. Neurobiol Dis. 2018 Jan;109(Pt A):127-136.
  • A novel form of amino (N)-terminal ubiquitination helps regulate the solubility and toxicity of disease-related proteins such as mutant huntingtin.  
Park SK, Hong JY, Arslan F, Kanneganti V, Patel B, Tietsort A, Tank EMH, Li X, Barmada SJ, Liebman SW. Overexpression of the essential Sis1 chaperone reduces TDP-43 effects on toxicity and proteolysis. PLoS Genet. 2017 May 22;13(5):e1006805.
  • In yeast and in mammalian neurons, the heat shock protein Sis1p or DNAJB1 prevents downstream toxicity from TDP-43 overexpression, in part by rescuing defective ubiquitin-dependent proteolysis.  
Gupta R, Lan M, Mojsilovic-Petrovic J, Choi WH, Safren N, Barmada S, Lee MJ, Kalb R. The Proline/Arginine Dipeptide from Hexanucleotide Repeat Expanded C9ORF72 Inhibits the Proteasome. eNeuro. 2017 Jan 31;4(1).
  • As shown in this manuscript, dipeptide repeat proteins, produced by repeat associated non-AUG (RAN) translation of the C9orf72 repeat, contribute to neurodegeneration in ALS and FTD by blocking protein turnover via the proteasome
Flores BN, Dulchavsky ME, Krans A, Sawaya MR, Paulson HL, Todd PK, Barmada SJ, Ivanova MI. Distinct C9orf72-Associated Dipeptide Repeat Structures Correlate with Neuronal Toxicity. PLoS One. 2016 Oct 24;11(10):e0165084.
  • These investigations show that small peptides generated by repeat associated non-AUG (RAN) translation of the C9orf72 hexanucleotide repeat assume unique conformations that are associated with cellular uptake and neurodegeneration in models of ALS and FTD.
Barmada SJ, Ju S, Arjun A, Batarse A, Archbold HC, Peisach D, Li X, Zhang Y, Tank EMH, Qiu H, Huang EJ, Ringe D, Petsko G, Finkbeiner S. Amelioration of toxicity in neuronal models of amyotrophic lateral sclerosis by hUPF1. Proc Natl Acad Sci U S A. 2015 Jun 8. pii: 201509744. 
  • This work provided the first evidence that nonsense mediated RNA decay plays a critical role in maintaining neuronal survival in models of ALS and FTD. 
Barmada SJ. Linking RNA dysregulation and neurodegeneration in amyotrophic lateral sclerosis. Neurotherapeutics. 2015 Feb 18.
  • A comprehensive review of how abnormalities in RNA processing lead to neuron loss in ALS, and potential opportunities for therapeutic intervention.
Barmada SJ, Serio A, Arjun A, Bilican B, Daub A, Ando DM, Tsvetkov A, Pleiss M, Li X, Peisach D, Shaw C, Chandran S, Finkbeiner S. Autophagy induction enhances TDP43 turnover and survival in neuronal ALS models. Nat Chem Biol. 2014 Aug;10(8):677-85.
  • In this study, we utilized optical pulse labeling to non-invasively measure the activity of autophagy and the turnover of TDP43 in living neurons. We also conducted an in silico screen for compounds capable of inducing autophagy, enhancing TDP43 clearance, and extending neuronal survival in ALS/FTD models.
Qiu H, Lee S, Shang Y, Wang WY, Au KF, Kamiya S, Barmada SJ, Finkbeiner S, Lui H, Carlton CE, Tang AA, Oldham MC, Wang H, Shorter J, Filiano AJ, Roberson ED, Tourtellotte WG, Chen B, Tsai LH, Huang EJ. ALS-associated mutation FUS-R521C causes DNA damage and RNA splicing defects. J Clin Invest. 2014 Mar 3;124(3):981-99.
  • This work describes a faithful in vivo model of ALS based on mutations in the RNA binding protein FUS, tracing neurodegeneration back to fundamental deficits in DNA damage repair and RNA processing.
Tsvetkov AS, Arrasate M, Barmada S, Ando DM, Sharma P, Shaby BA, Finkbeiner S. Proteostasis of polyglutamine varies among neurons and predicts neurodegeneration. Nat Chem Biol. 2013 Sep;9(9):586-92. 
  • Using a powerful single-cell approach, this work demonstrates a surprising amount of biological variability in the capacity of neurons to clear a mutant protein associated with neurodegeneration. Neurons that demonstrated intrinsically high protein turnover were longer lived, indicating that strategies aimed at stimulating protein clearance mechanisms may be broadly therapeutic.
Serio A, Bilican B, Barmada SJ, Ando DM, Zhao C, Siller R, Burr K, Haghi G, Story D, Nishimura AL, Carrasco MA, Phatnani HP, Shum C, Wilmut I, Maniatis T, Shaw CE, Finkbeiner S, Chandran S. Astrocyte pathology and the absence of non-cell autonomy in an induced pluripotent stem cell model of TDP-43 proteinopathy. Proc Natl Acad Sci U S A. 2013 Mar 19;110(12):4697-702. 
  • This report outlines an efficient method for generating astrocytes from human induced pluripotent stem cells. Surprisingly, astrocytes from human ALS patients carrying a TDP43 mutation survived poorly, suggesting that the mutation is not only toxic to neurons but also to glia.
Armakola M, Higgins MJ, Figley MD, Barmada SJ, Scarborough EA, Diaz Z, Fang X, Shorter J, Krogan NJ, Finkbeiner S, Farese RV Jr, Gitler AD. Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease models. Nat Genet. 2012 Dec;44(12):1302-9.
  • An unbiased yeast screen showed that loss of Dbr1, an enzyme responsible for unwinding RNA lariats formed after intron excision, prevents cell death in models of ALS and FTD. Lack of Dbr1 resulted in the accumulation of lariats that bound excess TDP43 and prevented downstream toxicity in yeast and in primary neuron disease models.
Martens LH, Zhang J, Barmada SJ, Zhou P, Kamiya S, Sun B, Min SW, Gan L, Finkbeiner S, Huang EJ, Farese RV Jr. Progranulin deficiency promotes neuroinflammation and neuron loss following toxin-induced injury. J Clin Invest. 2012 Nov 1;122(11):3955-9.
  • This work shows that progranulin has broad neuroprotective functions in vitro and in vivo, providing a potential explanation for the neurodegeneration observed in individuals with progranulin mutations, a common cause of inherited FTD.
Bilican B, Serio A, Barmada SJ, Nishimura AL, Sullivan GJ, Carrasco M, Phatnani HP, Puddifoot CA, Story D, Fletcher J, Park IH, Friedman BA, Daley GQ, Wyllie DJ, Hardingham GE, Wilmut I, Finkbeiner S, Maniatis T, Shaw CE, Chandran S. Mutant induced pluripotent stem cell lines recapitulate aspects of TDP-43 proteinopathies and reveal cell-specific vulnerability. Proc Natl Acad Sci U S A. 2012 Apr 10;109(15):5803-8.
  • In one of the first models of ALS utilizing neurons derived from human induced pluripotent stem cells, here we showed that neurons carrying a TDP43 mutation associated with familial ALS accumulated TDP43 and demonstrated an intrinsic survival deficit.
Barmada SJ, Finkbeiner S. Pathogenic TARDBP mutations in amyotrophic lateral sclerosis and frontotemporal dementia: disease-associated pathways. Rev Neurosci. 2010;21(4):251-72.
  • Here, we describe several potential mechanisms by which mutations in the glycine-rich domain of TDP43 result in neurodegeneration and the clinical syndromes of ALS and FTD. 
Barmada SJ, Skibinski G, Korb E, Rao EJ, Wu JY, Finkbeiner S. Cytoplasmic mislocalization of TDP-43 is toxic to neurons and enhanced by a mutation associated with familial amyotrophic lateral sclerosis. J Neurosci. 2010 Jan 13;30(2):639-49.
  • This study showed that the two most important predictors of cell death in models of ALS and FTD are the amount and localization of TDP43. Disease-associated mutations in TDP43 promoted cytoplasmic localization of the protein, highlighting a key mechanism that could contribute to neurodegeneration in familial ALS and FTD.