*: These authors have contributed equally to this work.
Research articles (bioRxiv)
Pircs K, Drouin-Ouellet J, Gil J, Rezeli M, Grassi DA, Garza R, Sharma Y, St-Amour I, Jönsson ME, Johansson PA, Harris K, Vuono R, Stoker T, Hersbach BA, Sharma K, Lagerwall J, Lagerström S, Storm P, Horváth V, Hébert 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’s disease
In this preprint we use direct reprogramming of fibroblasts to neurons to investigate disease-phenotypes in induced neurons (iNs) from patients with Huntington’s 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) – 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.
Drouin-Ouellet J, Pircs K, Legault EM, Birtele M, Nilsson F, Shrigley S, Pereira M, Storm P, Sharma Y, Vuono R, Stoker TB, Jakobsson J, Barker RA, Parmar M. (2021) Age-related pathological impairments in induced neurons derived from patients with idiopathic Parkinson’s disease
In this preprint we show that we can detect disease-relevant impairments in autophagy in the reprogrammed neurons from idiopathic Parkinson’s 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.
Johansson PA, Brattås PL, Douse CH, Hsieh P, Pontis J, Grassi D, Garza R, Jönsson ME, Atacho DAM, Pircs K, Eren F, Sharma Y, Johansson JG, Trono D, Eichler EE, Jakobsson J (2020) A human-specific structural variation at the ZNF558 locus controls a gene regulatory network during forebrain development
Davegårdh C, Säll J, Benrick A, Broholm C, Volkov P, Perfilyev A, Henriksen TI, Wu Y, Hjort L, Brøns C, Hansson O, Pedersen M, Würthner 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
Jönsson ME, Garza R, Sharma Y, Petri R, Södersten E, Johansson JG, Johansson PA, Atacho DAM, Pircs K, Madsen 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 Embo Journal
Brattås PL, Hersbach BA, Madsen S, Petri R, Jakobsson J, Pircs K (2020) Impact of differential and time-dependent autophagy activation on therapeutic efficacy in a model of Huntington disease Autophagy
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. Press release, Press release II
Jönsson ME, Brattås PL, Gustafsson C, Petri R, Yudovich D, Pircs K, Vershuere S, Madson S, Hansson J, Larsson J, Månsson R, Meissner A, Jakobsson J (2019) Activation of neuronal genes via LINE-1 elements upon global DNA demethylation in human neural progenitors Nature Communications
Petri R, Brattås PL, Sharma Y, Jönsson ME, Pircs K, Bengzon J, Jakobsson J (2019) LINE-2 transposable elements are a source of functional human microRNAs and target sites Plos Genetics
Kutsche LK, Gysi DM, Fallmann J, Lenk K, Petri R, Swiersy A, Klapper SD, Pircs K, Khattak S, Stadler PF, Jakobsson J, Nowick K, Busskamp V (2018) Combined Experimental and System-Level Analyses Reveal the Complex Regulatory Network of miR-124 during Human Neurogenesis Cell Systems
Pircs K, Petri R, Madsen S, Brattås PL, Vuono R, Ottosson RD, St-Amour I, Hersbach AB, Matusiak-Brückner M, Hult Lundh S, Petersén Å, Déglon N, Hébert SS, Parmar M, Barker AR, Jakobsson J (2018) Huntingtin aggregation impairs autophagy leading to Argonaute-2 accumulation and global microRNA dysregulation Cell Reports
In this paper we report that aggregation of the mutant huntingtin protein, a hallmark of Huntington’s 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’s disease. Press release; Article of the Year Award
Shrigley S, Pircs K, Barker AR, Parmar M, Drouin-Ouellet J (2018) Simple Generation of a High Yield Culture of Induced Neurons from Human Adult Skin Fibroblasts. J. Vis. Exp.
In this paper and video journal we describe a single vector-based method to generate induced neurons (iNs) from dermal fibroblasts obtained from adult human donors. Since the publishing date 5th February, 2018, the video has already been viewed over 3800 times. I was involved in all of the different experiments, the writing and also performed the FACS sorting chapter in the video. I would like to highlight that this paper has been published without the contribution of my current supervisor (Dr. Johan Jakobsson) during my Postdoc years.
Drouin-Ouellet J*, Lau S*, Brattås PL, Rylander Ottosson D, Pircs K, Grassi D, Collins ML, Vuono R, Sjöland AA, Westergren-Thorsson G, Graff C, Minthon L, Toresson H, Barker AR, Jakobsson J, Parmar M (2017) REST suppression mediates neural conversion of adult human fibroblasts via microRNA dependent and independent pathways EMBO Molecular Medicine.
In this paper we developed an optimized one-step method to efficiently reprogram adult human fibroblasts using a single-vector system. We also demonstrate that it is possible to obtain iNs of high yield and purity from aged individuals with a range of familial and sporadic neurodegenerative disorders including Parkinson's, Huntington's (HD), as well as Alzheimer's disease. I have performed all the relevant data using iNs derived from an HD patient after optimization of culture conditions. I have also helped in setting up and optimizing the iN purification experiments using FACS sorting.
Petri R, Pircs K, Jönsson ME, Akerblom M, Brattås PL, Klussendorf T, Jakobsson J. (2017) let-7 regulates radial migration of new-born neurons through positive regulation of autophagy. Embo Journal.
This paper is my first paper produced during my Postdoc years in Sweden, where I introduced autophagy to the group. I have designed, performed and analyzed all autophagy related experiments including TEM, immunostainings, rescue data with TFEB and Becn1. Altogether, we have revealed a miRNA-dependent link between autophagy and adult neurogenesis with implications for neurodegenerative diseases where these processes are impaired.
Takáts Sz, Varga Á, Pircs K, Juhász G. (2015) Loss of Drosophila Vps16A enhances autophagosome formation through reduced TOR activity Autophagy.
Takats Sz*, Pircs K*,Nagy P, Varga A, Karpati M, Hegedus K, Kramer H, Kovacs A, Sass M, Juhasz G. (2014) Interaction of the HOPS complex with Syntaxin 17 mediates autophagosome clearance in Drosophila Mol Biol Cell.
Nagy P, Hegedus K, Pircs K, Varga A, Juhasz G. (2014) Different effects of Atg2 and Atg18 mutations on Atg8a and Atg9 trafficking during starvation in Drosophila FEBS Letters.
Nagy P*, Karpati M*, Varga A, Pircs K, Venkei Zs, Takats Sz, Varga K, Erdi B, Hegedus K, Juhasz G. (2014) FIP200 promotes phagophore assembly at perilysosomal p62/Ref(2)P aggregates by activation of Atg1 in Drosophila Autophagy.
Nagy P, Pircs K, Varga A, Hegedus K, Juhász G. (2013) Myc-driven overgrowth requires unfolded protein response-mediated induction of autophagy and antioxidant responses in Drosophila melanogaster. PloS Genetics.
Low P*, Varga A*, Pircs K, Nagy P, Szatmari Zs, Sass M, Juhasz G. (2013) Impaired proteasomal degradation enhances autophagy via hypoxia signaling in Drosophila. BMC Cell Biology.
Takats Sz, Nagy P, Varga A, Pircs K, Karpati M, Varga K, Kovacs A, Hegedus K, Juhasz G. (2013) Autophagosomal Syntaxin17-dependent lysosomal degradation maintains neuronal function in Drosophila. J Cell Biol.
This paper is my most cited one (205 cites) where we revealed the molecular mechanism underlying autophagosomal fusion events and show that lysosomal degradation and recycling of sequestered autophagosome content is crucial to maintain proper functioning of the nervous system. I performed in this project all of the immunostainings and analyzed the microscopy data and performed statistical analysis too.
Pircs K, Nagy P, Varga A, Venkei Z, Erdi B, Hegedus K, Juhasz G. (2012) Advantages and limitations of different p62-based assays for estimating autophagic activity in Drosophila. PloS One.
This paper is the first of my first author papers. We compared different experimental approaches for using p62 assays in Drosophila larvae. We produced a p62 antibody in-house, which has been highly cited and commonly used in the fly field ever since. We have also highlighted the advantages and limitations of commonly used p62 assays, which have been applicable also to other cells and organisms used in autophagy research.
Erdi B, Nagy P, Zvara A, Varga A, Pircs K, Menesi D, Puskas LG, Juhasz G. (2012) Loss of the starvation-induced gene Rack1 leads to glycogen deficiency and impaired autophagic responses in Drosophila. Autophagy.
DJ Klionsky, AK Abdel-Aziz, S Abdelfatah, M Abdellatif, A Abdoli, S Abel, et al. (2021) Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition) Autophagy
Pircs K*, Petri R*, Jakobsson J (2018) Crosstalk between MicroRNAs and Autophagy in Adult Neurogenesis: Implications for Neurodegenerative Disorders Brain Plasticity
Drouin-Ouellet J*, Pircs K*, Barker AR, Jakobsson J, Parmar M (2017) Direct neuronal reprogramming for disease modeling studies using patient-derived neurons: What have we learned? Frontiers in Neuroscience
Here we reviewed published literature on the work that has been undertaken using induced neurons (iNs) to model human brain disorders. As disease-modelling studies using direct neuronal reprogramming approach are becoming more widely adopted, we also define the criteria that are used to define the iNs, especially in relation to the extent to which they are mature adult neurons.