Harnessing the mitochondrial vulnerability of neurons from Huntington´s disease patients for uncovering novel therapeutic targets

• Applicant: Professor Alessandro Prigione, Ph.D.
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 423776278

• Final Report Year: 2024

Final Report Abstract

In our project, we have demonstrated that the technology of iPSC reprogramming can be used to investigate the impact of HD on neurodevelopment. We have identified a novel target of intervention CHCHD2, which impacts neurodevelopment through a mitochondrial-related mechanism. Hence, mitochondrial dysfunction could represent a key mechanistic aspect in the early establishment of HD pathogenesis. We believe that our findings are important not only for the scientific community in the field of stem cells, HD, and mitochondria, but may also be worth sharing with the patient community and the general public. HD is a rare incurable disease and therefore it is important to increase awareness in the public. Affected patients and related families may be interested to hear about our scientific advances that have the potential to help establish new potential treatment options to some of the affected individuals.

Publications

• Bioenergetic Profiling of Human Pluripotent Stem Cells. Methods in Molecular Biology, 391-403. Springer US.
  Inak, Gizem; Henke, Marie-Thérèse & Prigione, Alessandro
  
• Defective metabolic programming impairs early neuronal morphogenesis in neural cultures and an organoid model of Leigh syndrome. Nature Communications, 12(1).
  Inak, Gizem; Rybak-Wolf, Agnieszka; Lisowski, Pawel; Pentimalli, Tancredi M.; Jüttner, René; Glažar, Petar; Uppal, Karan; Bottani, Emanuela; Brunetti, Dario; Secker, Christopher; Zink, Annika; Meierhofer, David; Henke, Marie-Thérèse; Dey, Monishita; Ciptasari, Ummi; Mlody, Barbara; Hahn, Tobias; Berruezo-Llacuna, Maria; Karaiskos, Nikos ... & Prigione, Alessandro
  
• Generation of Human Brain Organoids for Mitochondrial Disease Modeling. Journal of Visualized Experiments(172).
  Le, Stephanie; Petersilie, Laura; Inak, Gizem; Menacho-Pando, Carmen; Kafitz, Karl W.; Rybak-Wolf, Agnieszka; Rajewsky, Nikolaus; Rose, Christine R. & Prigione, Alessandro
  
• Generation of Human iPSC-derived Neural Progenitor Cells (NPCs) as Drug Discovery Model for Neurological and Mitochondrial Disorders. BIO-PROTOCOL, 11(5).
  Zink, Annika; Lisowski, Pawel & Prigione, Alessandro
  
• Mitochondria in Neurogenesis: Implications for Mitochondrial Diseases. Stem Cells, 39(10), 1289-1297.
  Brunetti, Dario; Dykstra, Werner; Le, Stephanie; Zink, Annika & Prigione, Alessandro
  
• A call for consensus guidelines on monitoring the integrity of nuclear and mitochondrial genomes in human pluripotent stem cells. Stem Cell Reports, 17(4), 707-710.
  Rossi, Andrea; Lickfett, Selene; Martins, Soraia & Prigione, Alessandro
  
• A Novel Gene Controls a New Structure: PiggyBac Transposable Element-Derived 1, Unique to Mammals, Controls Mammal-Specific Neuronal Paraspeckles. Molecular Biology and Evolution, 39(10).
  Raskó, Tamás; Pande, Amit; Radscheit, Kathrin; Zink, Annika; Singh, Manvendra; Sommer, Christian; Wachtl, Gerda; Kolacsek, Orsolya; Inak, Gizem; Szvetnik, Attila; Petrakis, Spyros; Bunse, Mario; Bansal, Vikas; Selbach, Matthias; Orbán, Tamás I.; Prigione, Alessandro; Hurst, Laurence D. & Izsvák, Zsuzsanna
  
• Generation of induced pluripotent stem cells from three individuals with Huntington‘s disease. Stem Cell Research, 65, 102976.
  Miller, Duncan C.; Lisowski, Pawel; Lickfett, Selene; Mlody, Barbara; Bünning, Miriam; Genehr, Carolin; Ulrich, Claas; Wanker, Erich E.; Diecke, Sebastian; Priller, Josef & Prigione, Alessandro
  
• High-content analysis of neuronal morphology in human iPSC-derived neurons. STAR Protocols, 3(3), 101567.
  Lickfett, Selene; Menacho, Carmen; Zink, Annika; Telugu, Narasimha Swamy; Beller, Mathias; Diecke, Sebastian; Cambridge, Sidney & Prigione, Alessandro
  
• High-content screening of mitochondrial polarization in neural cells derived from human pluripotent stem cells. STAR Protocols, 3(3), 101602.
  Zink, Annika; Haferkamp, Undine; Wittich, Annika; Beller, Mathias; Pless, Ole & Prigione, Alessandro
  
• Activated microglia and neuroinflammation as a pathogenic mechanism in Leigh syndrome. Frontiers in Neuroscience, 16.
  Daneshgar, Nastaran; Leidinger, Mariah R.; Le, Stephanie; Hefti, Marco; Prigione, Alessandro & Dai, Dao-Fu
  
• Generation of an induced pluripotent stem cell line from a Huntington’s disease patient with a long HTT-PolyQ sequence. Stem Cell Research, 68, 103056.
  Miller, Duncan C.; Lisowski, Pawel; Genehr, Carolin; Wanker, Erich E.; Priller, Josef; Prigione, Alessandro & Diecke, Sebastian
  
• Modeling mitochondrial DNA diseases: from base editing to pluripotent stem‐cell‐derived organoids. EMBO reports, 24(4).
  Tolle, Isabella; Tiranti, Valeria & Prigione, Alessandro
  
• Mutant Huntingtin impairs neurodevelopment in human brain organoids through CHCHD2-mediated neurometabolic failure.
  Lisowski, Pawel; Lickfett, Selene; Rybak-Wolf, Agnieszka; Le, Stephanie; Dykstra, Werner; Mlody, Barbara; Menacho, Carmen; Roth, Philipp; Richter, Yasmin; Kulka, Linda A. M.; Glazar, Petar; Wu, Haijia; Meierhofer, David; Legnini, Ivano; Otto, Max; Miller, Duncan; Neuendorf, Nancy; Hahn, Tobias; Telugu, Narasimha Swamy ... & Prigione, Alessandro
  
• A Standardized Nomenclature Design for Systematic Referencing and Identification of Animal Cellular Material. Animals, 14(11), 1541.
  Schrade, Lisa; Mah, Nancy; Bandrowski, Anita; Chen, Ying; Dewender, Johannes; Diecke, Sebastian; Hiepen, Christian; Lancaster, Madeline A.; Marques-Bonet, Tomas; Martinez, Sira; Mueller, Sabine C.; Navara, Christopher; Prigione, Alessandro; Seltmann, Stefanie; Sochacki, Jaroslaw; Sutcliffe, Magdalena A.; Zywitza, Vera; Hildebrandt, Thomas B. & Kurtz, Andreas
  
• Balancing neuronal activity to fight neurodevelopmental disorders. Trends in Neurosciences, 47(4), 241-242.
  Le, Stephanie; Menacho, Carmen & Prigione, Alessandro
  
• Mitochondrial DNA integrity and metabolome profile are preserved in the human induced pluripotent stem cell reference line KOLF2.1J. Stem Cell Reports, 19(3), 343-350.
  Dobner, Jochen; Nguyen, Thach; Dunkel, Andreas; Prigione, Alessandro; Krutmann, Jean & Rossi, Andrea