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Khurana V, Peng J, Chung CY, Auluck PK, Fanning S, Tardiff DF, Bartels T, Koeva M, Eichhorn SW, Benyamini H, Lou Y, Nutter-Upham A, Baru V, Freyzon Y, Tuncbag N, Costanzo M, San Luis BJ, Schöndorf DC, Barrasa MI, Ehsani S, Sanjana N, Zhong Q, Gasser T, Bartel DP, Vidal M, Deleidi M, Boone C, Fraenkel E, Berger B, Lindquist S. Genome-Scale Networks Link Neurodegenerative Disease Genes to α-Synuclein through Specific Molecular Pathways. Cell Syst. 2017 Feb 22;4(2):157-170.e14. Epub 2017 Jan 25 PubMed.
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Columbia University
Brandeis University
This duet of papers represents the swan song of one of the deepest thinkers into the fundamental biology of neurodegeneration, our recently departed friend Sue Lindquist, who sadly died a few months ago. The papers illustrate the magnificent creativeness and scope of her life’s work, integrating yeast, genomic, and computational biology with symphonic elegance.
In previous papers, Sue and her team had used such an integrative approach to identify molecular networks linked to individual proteinopathies, Aβ toxicity associated with Alzheimer’s (Treusch et al., 2011), and α-synuclein toxicity associated with Parkinson’s disease (Chung et al., 2013). Sue always believed that there must be mechanistic themes that overlie and unify these proteinopathies, and in fact, AD and PD are associated disorders that are converging more and more, in their histological and molecular makers, and ultimately in their clinical presentations. While the primary focus in the current papers is on α-synuclein, and they introduce a plethora of findings, we know she was especially pleased that they essentially confirmed her unfailing intuition: namely, that the proteinopathies observed in many neurodegenerative diseases appear driven by overlapping mechanistic pathways, especially at the level of cell biology. The two top pathways that emerge from these two papers as fundamental drivers of neurodegenerative diseases are endocytic trafficking and mRNA metabolism. More specifically, and what unsurprisingly is most interesting to us (Small and Petsko, 2015), retromer-related molecules were the dominant unifiers in the endocytic trafficking pathway, including retromer’s molecular core protein Vps35 (see especially Figure 3B in the second paper). While the entire multimodular retromer assembly seems to be a molecular point of convergence in PD and AD, genetic studies are beginning to explain how subtle biochemical differences in defects observed in the single molecule Vps35 can be linked more with one than the other (Rovelet-Lecrux et al., 2015). The systems biology approach taken by Sue Lindquist in these papers represents the latest, and certainly one of the most elegant, set of evidence in a rapidly solidifying case that endosomal trafficking is a cell biology pathway at the heart of the major neurodegenerative diseases.
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