Project 08:
Interplay between local translation of mitochondrial proteins and proteostasis in neurons
Irina Dudanova
E-Mail: irina.dudanova@uk-koeln.de
Phone: +49 221-478-98738
Center for Anatomy
Molecular Neurodegeneration Group
University Hospital Cologne
Angelika Harbauer
E-Mail: angelika.harbauer@bi.mpg.de
Phone: +49 89-8578-2083
Max Planck Institute for Biological Intelligence
Martinsried
Abstract
Mitochondrial dysfunction and impaired proteostasis are key hallmarks of neurodegenerative diseases. Most mitochondrial proteins are synthesized in the cytoplasm as precursors and then imported into the organelle. In neurons, a large portion of mitochondrial proteins found in axons are translated locally, which often occurs at ER-localized ribosomes. However, the proteostasis machinery that handles mitochondrial precursors in axons to transport them back to mitochondria remains to be clarified. In this project we aim to understand the dedicated molecular mechanism that is in place to handle locally translated mitochondrial proteins, and how this mechanism is affected in neurodegenerative diseases.
Project-relevant publications
Hees JT, Segura I, Schneider A, Schifferer M, Misgeld T, Harbauer AB (2024) ER-associated biogenesis of Pink1 preprotein for neuronal mitophagy. bioRxiv. [Preprint] https://doi.org/10.1101/2024.06.21.600039.
Hees JT, Wanderoy S, Lindner J, Helms M, Murali Mahadevan H, Harbauer AB (2024) Insulin signalling regulates Pink1 mRNA localization via modulation of AMPK activity to support PINK1 function in neurons. Nat Metab. 6(3):514-530.
Saha I, Yuste-Checa P, Da Silva Padilha M, Guo Q, Körner R, Holthusen H, Trinkaus VA, Dudanova I, Fernández-Busnadiego R, Baumeister W, Sanders DW, Gautam S, Diamond MI, Hartl FU, Hipp MS (2023) The AAA+ chaperone VCP disaggregates Tau fibrils and generates aggregate seeds in a cellular system. Nat Commun. 14(1):560.
Dudanova I (2022) Biosensors for studying neuronal proteostasis. Front Mol Neurosci. 15:829365.
Harbauer AB, Hees JT, Wanderoy S, Segura I, Gibbs W, Cheng Y, Ordonez M, Cai Z, Cartoni R, Ashrafi G, Wang C, Perocchi F, He Z, Schwarz TL (2022) Neuronal mitochondria transport Pink1 mRNA via synaptojanin 2 to support local mitophagy. Neuron. 110(9):1516-1531.e9.
Riera-Tur I, Schäfer T, Hornburg D, Mishra A, da Silva Padilha M, Fernández-Mosquera L, Feigenbutz D, Auer P, Mann M, Baumeister W, Klein R, Meissner F, Raimundo N, Fernández-Busnadiego R, Dudanova I (2021) Amyloid-like aggregating proteins cause lysosomal defects in neurons via gain-of-function toxicity. Life Sci Alliance. 5(3):e202101185.
Blumenstock S, Schulz-Trieglaff EK, Voelkl K, Bolender AL, Lapios P, Lindner J, Hipp MS, Hartl FU, Klein R, Dudanova I (2021) Fluc-EGFP reporter mice reveal differential alterations of neuronal proteostasis in aging and disease. EMBO J. 40(19):e107260.
Yuste-Checa P, Trinkaus VA, Riera-Tur I, Imamoglu R, Schaller TF, Wang H, Dudanova I, Hipp MS, Bracher A, Hartl FU (2021) The extracellular chaperone Clusterin enhances Tau aggregate seeding in a cellular model. Nat Commun. 12(1):4863.
Hosp F, Gutiérrez-Ángel S, Schaefer MH, Cox J, Meissner F, Hipp MS, Hartl FU, Klein R, Dudanova I, Mann M (2017) Spatiotemporal proteomic profiling of huntington's disease inclusions reveals widespread loss of protein function. Cell Rep. 21(8):2291-2303.
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