Mechanisms of Neurodegeneration

We are interested in investigating the pathogenic mechanisms associated with ALS (amyotrophic lateral sclerosis Within the last 30 years, several genes have been implicated in ALS, including the RNA-binding protein TAR DNA-binding Protein 43 (TDP-43) and the actin-binding protein profilin 1 (PFN1). However, the roles of these two proteins in the pathogenesis of the disease remain incompletely understood.

To address this, my laboratory employs biophysical and biochemical approaches to study the structure, dynamics, and binding activities of TDP-43 and PFN1. We integrate in vitro and in vivo studies of ALS-linked variants of these proteins to uncover how their functions are disrupted within the cellular environment.  

Relevant Publications

A Hydrophobic Core Stabilizes the Residual Structure in the RRM2 Intermediate State of the ALS-linked Protein TDP-43. Mackness BC, Morgan BR, Deveau LM, Kathuria SV, Zitzewitz JA, Massi F. J Mol Biol. 2024 Nov 15;436(22):168823. doi: 10.1016/j.jmb.2024.168823. Epub 2024 Oct 18.PMID: 39426615

Expression of ALS-PFN1 impairs vesicular degradation in iPSC-derived microglia. Funes S, Jung J, Gadd DH, Mosqueda M, Zhong J, Shankaracharya, Unger M, Stallworth K, Cameron D, Rotunno MS, Dawes P, Fowler-Magaw M, Keagle PJ, McDonough JA, Boopathy S, Sena-Esteves M, Nickerson JA, Lutz C, Skarnes WC, Lim ET, Schafer DP, Massi F, Landers JE, Bosco DA. Nat Commun. 2024 Mar 20;15(1):2497. doi: 10.1038/s41467-024-46695-w.PMID: 38509062 

ALS-linked PFN1 variants exhibit loss and gain of functions in the context of formin-induced actin polymerization. Schmidt EJ, Funes S, McKeon JE, Morgan BR, Boopathy S, O'Connor LC, Bilsel O, Massi F, Jégou A, Bosco DA. Proc Natl Acad Sci U S A. 2021 Jun 8;118(23):e2024605118. doi: 10.1073/pnas.2024605118.PMID: 34074767

Characterization of TDP-43 RRM2 Partially Folded States and Their Significance to ALS Pathogenesis. Tavella D, Zitzewitz JA, Massi F. Biophys J. 2018 Nov 6;115(9):1673-1680. doi: 10.1016/j.bpj.2018.09.011. Epub 2018 Sep 21.PMID: 30309612