Biology subjects

Hoogenraad, C.

Publications and source records attributed to Hoogenraad, C..

2 recordsLinked to original sources

bioRxiv2019

Deciphering the protein dynamics and molecular determinants of iPSC-derived neurons.

Neuronal development is a multistep process with different regulatory programs that shapes neurons to form dendrites, axons and synapses. To date, knowledge on neuronal development is largely based on murine data and largely restricted to the genomic and transcriptomic level. Advances in stem cell differentiation now enable the study of human neuronal development, and here we provide a mass spectrometry-based quantitative proteomic signature, at high temporal resolution, of human stem cell-derived neurons. To reveal proteomic changes during neuronal development we make use of two differentiation approaches, either by expression of neurogenin-2 (Ngn2) leading to glutamatergic induced neurons (iN) or via small molecule manipulations, leading to patterned motor neurons. Our analysis revealed key proteins that show significant expression changes (FDR <0.001) during neuronal differentiation. We overlay our proteomics data with available transcriptomic data during neuronal differentiation and show distinct, datatype-specific, signatures. Overall, we provide a rich resource of information on proteins associated with human neuronal development, and moreover, highlight several signaling pathways involved, such as Wnt and Notch.

neuroscience↗

bioRxiv2019

Fibril formation rewires interactome of the Alzheimer protein Tau by π-stacking

Aggregation of the Tau protein defines progression of neurodegenerative diseases, including Alzheimers Disease. Tau assembles into oligomers and fibrils. The molecular basis of their toxicity is poorly understood. Here we show that {pi}-stacking by Arginine side chains rewires the interactome of Tau upon aggregation. Oligomeric nano-aggregates scavenge the COPI complex, fibrils attract proteins involved in microtubule binding, RNA binding and phosphorylation. The aberrant interactors have disordered regions with unusual sequence features. Arginines are crucial to initiate such aberrant interactions. Remarkably, substitution of Arginines by Lysines abolishes scavenging, which indicates a key role for the pi-stacking of the Arginine side chain. The molecular chaperone Hsp90 tames such re-arrangements, which suggests that the natural protein quality control system can suppress aberrant interactions. Together, our data present a molecular mode of action for derailment of protein-protein interaction in neurodegeneration.\n\nHIGHLIGHTSO_LITau fibrils act as fishing net for proteins.\nC_LIO_LITau fibrils attract specific protein families associated with Alzheimer.\nC_LIO_LI{pi}-stacking by Arginines key for aberrant binding to Tau fibrils\nC_LIO_LIThe Hsp90 chaperone stalls fibril growth and alters interactome\nC_LI

biochemistry↗