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Research articles (bioRxiv)<\/span><\/strong><\/p>\n Danics L, Muralidharan C<\/span><\/span>,\u00a0 Varga \u00c1,<\/span>\u00a0\u00a0<\/a>Rezeli M<\/span><\/span>, Gil J, Abbas AA<\/span><\/span>, Pap \u00c1, Park SA,\u00a0Cserhalmi M<\/span><\/span>,\u00a0S\u0151th \u00c1<\/span><\/span>, Jamniczky D, Zsoldos R, Barker RA, R\u00f3na G, Drouin-Ouellet J, Mark\u00f3-Varga G, Darula Z, Pircs K. (2025) <\/span><\/span>Phosphoproteomic profiling reveals post-translational dysregulation in Huntington\u2019s disease patient-derived neurons<\/p>\n doi:<\/span>\u00a0https:\/\/doi.org\/10.1101\/2025.10.24.684372<\/a><\/p>\n In this work, we present the first phosphoproteomic analysis by mass spectrometry (P-MS) of human induced neurons (iNs) directly reprogrammed from Huntington\u2019s disease (HD) patient fibroblasts, integrated with matched proteomic and transcriptomic data from the same donors. We identify 177 significantly altered phosphopeptides, pointing to major signaling changes involving RNA splicing, autophagy, and stress-response pathways. Among these, MXRA8 shows a complete loss of phosphorylation at pS377 in HD-iNs, despite increased protein abundance. Kinase and co-IP analyses reveal autophagy-linked regulators and condition-specific MXRA8 interactors (e.g. LAMP1\/TGM2), supporting the role of altered phosphorylation in disrupted proteostasis in human HD neurons. This project provides a new P-MS resource for the HD community.<\/p>\n <\/p>\n Peer-reviewed original articles<\/span><\/strong><\/span><\/p>\n 2025 <\/a> <\/strong><\/p>\n Muralidharan C<\/span><\/span>,\u00a0 Zakar-Poly\u00e1k E<\/span><\/span>,\u00a0\u00a0<\/a>Adami A<\/span><\/span>,\u00a0Abbas AA<\/span><\/span>, Sharma Y<\/span><\/span>,\u00a0Garza R<\/span><\/span>,\u00a0Johansson JG<\/span><\/span>, Atacho DAM<\/span><\/span>, Renner \u00c9<\/span><\/span>,\u00a0<\/a>Palkovits M<\/span><\/span>, Kerepesi C<\/span><\/span>, Jakobsson J<\/span><\/span>, Pircs K. (2025) <\/span><\/span>Human brain cell-type-specific aging clocks based on single-nuclei transcriptomics, Advanced Science<\/strong><\/p>\n DOWNLOAD PDF<\/a><\/p>\n https:\/\/doi.org\/10.1002\/advs.202506109<\/a><\/p>\n <\/p>\n Kawamura T, <\/span><\/span>Kerepesi C, <\/span><\/span>Sarkar JP, <\/span><\/span>Torma F, <\/span><\/span>Bori Z, <\/span><\/span>Zhou L, <\/span><\/span>Bakonyi P, <\/span><\/span>Kolonics A, <\/span><\/span>Balogh L,<\/span><\/span> Higuchi M, <\/span><\/span>Pill\u00e1r V, <\/span><\/span>Pircs K, <\/span><\/span>Koch LG, <\/span><\/span>Britton SL, <\/span><\/span>Koltai E, <\/span><\/span>Radak Z. (2025) <\/span>Organ Specificity and Commonality of Epigenetic Aging in Low- and High-Running Capacity Rats, Aging Cell<\/strong><\/p>\n DOWNLOAD PDF<\/a><\/p>\n https:\/\/doi.org\/10.1111\/acel.70110<\/a><\/p>\n <\/p>\n 2024 <\/a> <\/strong><\/p>\n Li X, <\/span><\/span>Hernandez I, <\/span><\/span>Koyuncu S, <\/span><\/span>Kis B,\u00a0<\/span><\/span>H\u00e4ggblad M, <\/span><\/span>Lidemalm L, <\/span><\/span>Abbas AA, Sramk\u00f3 B<\/span>, <\/span><\/span>G\u00f6bl\u00f6s A, <\/span><\/span>Brautigam L, <\/span><\/span>Lucas JJ, <\/span><\/span>Carreras-Puigvert J, <\/span><\/span>H\u00fchn D, <\/span><\/span>Pircs K, <\/span><\/span>Vilchez D,<\/span><\/span> Fernandez-Capetillo O. <\/span>(2024) The anti-leprosy drug clofazimine reduces polyQ toxicity through activation of PPAR\u03b3, Lancet EBioMedicine<\/strong><\/p>\n DOWNLOAD pdf<\/a><\/p>\n doi: 10.1016\/j.ebiom.2024.105124<\/a><\/p>\n <\/p>\n 2023 <\/a> <\/strong><\/p>\n R\u00f6nn T, Ofori JK, Perfilyev A, Hamilton A, Pircs K, Eichelmann F, Garcia-Calzon S, Karagiannopoulos A, Stenlund H, Wendt A, Volkov P, Schulze MB, Mulder H, Eliasson L, Ruhrmann S, Bacos K, Ling C. (2023) Genes with epigenetic alterations in human pancreatic islets impact mitochondrial function, insulin secretion, and type 2 diabetes, Nature Communications<\/strong><\/p>\n DOWNLOAD pdf<\/a><\/p>\n doi: 10.1038\/s41467-023-43719-9.<\/span><\/a><\/p>\n <\/p>\n 2022 <\/a> <\/strong><\/p>\n Drouin-Ouellet J, Legault EM, Nilsson F, Pircs K, Bouquety J, Petit F, Shrigley S, Birtele M, Pereira M, Storm P, Nilsson F, Sharma Y, Bruzelius A, Vuono R, Kele M, Stoker TB, Rylander Ottosson D, Falk A, Jakobsson J, Barker RA, Parmar M. (2022) Age-related pathological impairments in directly reprogrammed dopaminergic neurons derived from patients with idiopathic Parkinson\u2019s disease, Stem Cell Reports<\/strong><\/p>\n DOWNLOAD pdf<\/a><\/p>\n doi: 0.1016\/j.stemcr.2022.08.010<\/span><\/a><\/p>\n In this paper we show that we can detect disease-relevant impairments in autophagy in the reprogrammed neurons from idiopathic Parkinson\u2019s disease patients but not in the fibroblasts. Some phenotypes are specific to the dopaminergic neurons whereas others were present in both dopaminergic and non-dopaminergic neurons. The pathology varies as a function of age of patient and to some extent tau haplotype – a genetic variant that is known to influence the risk of getting PD and its clinical course. Lastly, we found that these deficits were associated with the age of the patients.<\/p>\n <\/p>\n Petry S, Keraudren R, Nateghi B, Loiselle A, Pircs K, Jakobsson J, Sephton C, Langlois M, St-Amour I, H\u00e9bert SS (2022) Widespread alterations in microRNA biogenesis in human Huntington\u2019s disease putamen, Acta Neuropathologica Communications<\/strong><\/p>\n download pdf<\/a><\/p>\n doi: 10.1186\/s40478-022-01407-7<\/a><\/p>\n <\/p>\n 2021 <\/a> <\/strong><\/p>\n Pircs K, Drouin-Ouellet J, Gil J, Rezeli M, Grassi DA, Garza R, Sharma Y, St-Amour I, J\u00f6nsson ME, Johansson PA, Harris K, Vuono R, Stoker T, Hersbach BA, Sharma K, Lagerwall J, Lagerstr\u00f6m S, Storm P, Horv\u00e1th V, H\u00e9bert SS, Marko-Varga Gy, Parmar M, Barker RA, Jakobsson J. (2021) Distinct sub-cellular autophagy impairments occur independently of protein aggregation in induced neurons from patients with Huntington\u2019s disease, Brain<\/strong><\/p>\n download pdf<\/a><\/p>\n doi: https:\/\/doi.org\/10.1093\/brain\/awab473<\/a><\/p>\n In this paper we use direct reprogramming of fibroblasts to neurons to investigate disease-phenotypes in induced neurons (iNs) from patients with Huntington\u2019s disease. iNs are an excellent model-system to study pathological mechanisms in neurodegenerative disorders – these cells retain epigenetic age. Interestingly, we find that HD-iNs display an increased biological age determined by DNAmet analysis. We were able to detect clear disease-related phenotypes when studying iNs from individuals with CAG repeats in the range normally seen in clinic in patients (39-50) \u2013 something which has not been achieved with iPSC-modelling. We found a specific subcellular impairment of autophagy localized to the neurites, characterized by an impairment in the CAMKK-AMPK-signaling pathway. Our findings have clear translational implications for the treatment of HD. With CRISPRi-based editing we reveal that both the wtHTT and mHTT allele plays a role in the control\/impairment of autophagy. This has direct links to the ongoing anti-sense clinical trials in HD. Our results points to the use of allele specific silencing-based therapies. Press release<\/a><\/p>\n <\/p>\n Johansson P.A., Bratt\u00e5s P.L., Douse Ch.H., Hsieh PH, Adami A, Pontis J, Grassi D, Garza R, Sozzi E, Cataldo R, J\u00f6nsson M.E., Atacho D.A.M., Pircs K, Eren F, Sharma Y, Johansson J, Fiorenzano A, Parmar M, Fex M, Trono D, Eichler E.E., Jakobsson J (2021) A cis-acting structural variation at the ZNF558 locus controls a gene regulatory network in human brain development, Cell Stem Cell<\/strong><\/p>\n download pdf<\/a><\/p>\n https:\/\/doi.org\/10.1016\/j.stem.2021.09.008<\/a><\/p>\n Press release I,\u00a0<\/a>Press release II<\/a><\/p>\n <\/p>\n Daveg\u00e5rdh C, S\u00e4ll J, Benrick A, Broholm C, Volkov P, Perfilyev A, Henriksen TI, Wu Y, Hjort L, Br\u00f8ns C, Hansson O, Pedersen M, W\u00fcrthner JU, Pfeffer K, Nilsson E, Vaag A, Stener-Victorin E, Pircs K, Scheele C, Ling C (2021) VPS39-deficiency observed in type 2 diabetes impairs muscle stem cell differentiation via altered autophagy and epigenetics Nature Communications<\/strong><\/p>\n download pdf<\/a><\/p>\n https:\/\/doi.org\/10.1038\/s41467-021-22068-5<\/a><\/p>\n <\/p>\n J\u00f6nsson ME, Garza R, Sharma Y, Petri R,\u00a0S\u00f6dersten E, Johansson JG,\u00a0 Johansson PA, Atacho DAM,\u00a0Pircs K,\u00a0Madsen S, Yudovich D, Ramakrishnan R, Holmberg J, Larsson J, Jern P, Jakobsson J (2021) Activation of endogenous retroviruses during brain development causes an inflammatory response\u00a0Embo Journal<\/strong><\/p>\n download pdf<\/a><\/p>\n https:\/\/doi.org\/10.15252\/embj.2020106423<\/a><\/p>\n Press release<\/a><\/p>\n <\/p>\n 2020 <\/a> <\/strong><\/p>\n Bratt\u00e5s PL, Hersbach BA, Madsen S, Petri R, Jakobsson J,\u00a0Pircs K\u00a0(2020)\u00a0Impact of differential and time-dependent autophagy activation on therapeutic efficacy in a model of Huntington disease\u00a0Autophagy<\/strong><\/p>\n download pdf<\/a><\/p>\n https:\/\/doi.org\/10.1080\/15548627.2020.1760014<\/a><\/p>\n In this paper we used a mouse model of Huntington disease, where we inject neuron specific viral vectors into the striatum to drive the over-expression of either wild type, or mutant HTT. Our results demonstrate that the targets used to activate autophagy, as well as the timing of autophagy activation, are crucial for achieving efficient therapeutic effects.\u00a0Press release,\u00a0<\/a>Press release II<\/a><\/p>\n <\/p>\n 2019 <\/a> <\/strong><\/p>\n J\u00f6nsson ME, Bratt\u00e5s PL, Gustafsson C, Petri R, Yudovich D,\u00a0Pircs K, Vershuere S, Madson S, Hansson J, Larsson J, M\u00e5nsson R, Meissner A, Jakobsson J (2019)\u00a0 Activation of neuronal genes via LINE-1 elements upon global DNA demethylation in human neural progenitors\u00a0Nature Communications\u00a0<\/strong><\/p>\n download pdf<\/a><\/p>\n doi.org\/10.1038\/s41467-019-11150-8<\/a><\/p>\n <\/p>\n Petri R, Bratt\u00e5s PL, Sharma Y, J\u00f6nsson ME,\u00a0Pircs K, Bengzon J, Jakobsson J (2019) LINE-2 transposable elements are a source of functional human microRNAs and target sites\u00a0Plos Genetics<\/strong><\/p>\n download pdf<\/a><\/p>\n doi.org\/10.1371\/journal.pgen.1008036<\/a><\/p>\n <\/p>\n 2018 <\/a> <\/strong><\/p>\n Kutsche LK,\u00a0Gysi DM,\u00a0Fallmann J,\u00a0Lenk K,\u00a0Petri R,\u00a0Swiersy A,\u00a0Klapper SD,\u00a0Pircs K,\u00a0Khattak S,\u00a0Stadler PF,\u00a0Jakobsson J,\u00a0Nowick K,\u00a0Busskamp V (2018)\u00a0Combined\u00a0Experimental\u00a0and\u00a0System-Level\u00a0Analyses\u00a0Reveal\u00a0the\u00a0Complex\u00a0Regulatory\u00a0Network\u00a0of\u00a0miR-124\u00a0during\u00a0Human\u00a0Neurogenesis\u00a0Cell Systems<\/strong><\/p>\n download pdf<\/a><\/p>\n doi: 10.1016\/j.cels.2018.08.011<\/a><\/p>\n \u00a0<\/p>\n Pircs K, Petri R, Madsen S, Bratt\u00e5s PL, Vuono R, Ottosson RD, St-Amour I, Hersbach AB, Matusiak-Br\u00fcckner M, Hult Lundh S, Peters\u00e9n \u00c5, D\u00e9glon N, H\u00e9bert SS, Parmar M, Barker AR, Jakobsson J (2018) Huntingtin aggregation impairs autophagy leading to Argonaute-2 accumulation and global microRNA dysregulation\u00a0Cell Reports<\/strong><\/p>\n download pdf<\/a><\/p>\n doi: 10.1016\/j.celrep.2018.07.017<\/a><\/p>\n In this paper we report that aggregation of the mutant huntingtin protein, a hallmark of Huntington\u2019s disease proteinopathy, impairs macroautophagy leading to Argonaute-2 accumulation and global dysregulation of microRNAs. These results indicate that autophagy not only influences protein aggregation, but also directly contributes to the global alterations of post-transcriptional networks in Huntington\u2019s disease.\u00a0Press release;\u00a0<\/a>Article of the Year Award<\/a>\u00a0, Press release<\/a><\/p>\n <\/p>\n Shrigley S,\u00a0Pircs K, Barker AR, Parmar M, Drouin-Ouellet J (2018) Simple Generation of a High Yield Culture of Induced Neurons from Human Adult Skin Fibroblasts.