Song Lab: Structural Origins of Neurodegeneration and Therapeutic Approaches

Overview

The Song Laboratory is a young, energetic, and innovative group in the Department of Neurology at Mass General Hospital and Harvard Medical School. We are associated with MassGeneral Institute for Neurodegenerative Disease (MIND) and are affiliated with the Massachusetts Alzheimer's Disease Research Center (MADRC). We also have active summer research programs at the Marine Biological Laboratory at Woods Hole and exciting collaborations with various laboratories at Harvard and beyond.

We are particularly interested in Molecular mechanisms driving selective neuronal vulnerability in neurodegenerative diseases, with a primary focus on amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer’s disease (AD), and Huntington’s Disease (HD). We study how misfolded and aggregation-prone proteins—including tau, TDP-43, and C9ORF72-derived dipeptide repeat proteins—disrupt key cellular pathways such as nucleocytoplasmic transport, cytoskeletal dynamics, organelle homeostasis, and axonal transport. Using complementary approaches that span primary neuronal cultures, human iPSC-derived neurons, transgenic mouse models, quantitative proteomics, advanced imaging, and AI-driven image analysis tools, we aim to define early pathogenic events that precede overt neurodegeneration. A central goal of our work is to understand why specific neuronal populations degenerate while others are relatively spared, and to translate these mechanistic insights into biomarker strategies and therapeutic targets. Through integration of molecular biology, systems-level analysis, and computational innovation, our lab seeks to bridge fundamental discovery with translational impact in neurodegenerative disease.

Research Projects

• Structure and Function of Intrinsically Disordered Proteins and Regions.
• Protein Misfolding and Chaperones in Tauopathies and ALS.
• Neuronal Cytoskeletal Dynamics and Stability.
• Intracellular Trafficking, Motor Proteins, and Neuronal Signaling in Health and Disease.
• Synaptic Actions of Misfolded Proteins and Calcium Signaling.
• Molecular Mechanisms and Potential Therapeutic Approaches for Neurodegenerative Diseases (e.g., ALS, AD, HD, etc.).
• Development of multi-omics studies, multiplexed and high-content imaging techniques, and super-resolution imaging methods in various animal and human model systems.

Research Team

Triscia Afihene
Undergraduate Researcher

Elaina Bashaw
Research Associate

Etash Bhat
Undergraduate Researcher

Chance Bonfanti
Undergraduate Researcher

Soukayna Boulaassafre
PhD Student

Prarthna Chabria
Research Associate

Zareh Dechkounian
Undergraduate Researcher

Verheijen, Lambertus Marie
Visiting Postdoctoral Fellow

Ishan Makkar
Summer Researcher

Lucy Qian
Undergraduate Researcher

Mitul Saha
Senior Computation Scientist

Publications

View publications

Selected Publications

• Jiang X, Schaeffer L, Patni D, Russo T, Lee CZ, Aguilar C, Marques C, Jansen-West K, Hruska-Plochan M, Ray-Soni A, Lim SM, Held A, Yue M, Castellanos Otero P, Aryal S, Beaussant HDAM, Basu H, Takakuwa H, Daughrity LM, Ramesh N, Da Costa P, A A Quadros AR, Nolan M, Reyes CJF, Wheeler H, Moran LC, Griesman G, Wymann B, Trombetta BA, Lopez-De-Silanes ES, Canori M, Krishnan G, Vieira Souza Da Silva Y, Eriani G, Albers MW, Arnold SE, Song Y, Jain A, Chiu IM, Zhang YJ, Gao FB, Wainger BJ, Polymenidou M, Petrucelli L, Martin F, Lagier-Tourenne C. Blocking RAN translation without altering repeat RNAs rescues C9ORF72-related ALS and FTD phenotypes. Science. 2026 Feb 5;391(6785):eadv2600. doi: 10.1126/science.adv2600. Epub 2026 Feb 5. PubMed PMID: 41643021.
• Georgescauld F, Okekenwa S, Boyd T, Donahue C, Quittot N, Dickson JR, Fan Z, Brady S, Blackstone C, Hyman B, Song Y. Dynamic conformational ensembles of soluble Tau encode neuronal toxicity prior to aggregation. bioRxiv. 2026 Jan 27;. doi: 10.64898/2026.01.26.701882. PubMed PMID: 41659508; PubMed Central PMCID: PMC12873973.
• Saez-Calveras N, Verheijen BM, Morgan N, Hill E, Taylor S, Oyanagi K, Kakita A, Song Y, Joachimiak LA, Vaquer-Alicea J, Diamond MI, Lu Y. Guam amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) features CTE-like tau seeds in brain and spinal cord. bioRxiv. 2025 Dec 25;. doi: 10.64898/2025.12.22.696002. PubMed PMID: 41509476; PubMed Central PMCID: PMC12776150.
• Bhat E, Selvan S, Okekenwa S, Dechkounian Z, Lin V, Nakano M, Saha M, Song Y. Lightweight open-source fine-tuning of SAM2 enables domain-specific microscopy segmentation. bioRxiv. 2025 Nov 10;. doi: 10.1101/2025.11.08.687405. PubMed PMID: 41292892; PubMed Central PMCID: PMC12642685.
• Fang R, Bai L, Verheijen BM, Li B, Dong K, Paulo JA, Zhou M, Chu YC, Song Y, Sherman MY, Gygi S, Field CM, Mitchison TJ, Lu Y. Episodic transport of protein aggregates achieves a positive size selectivity in aggresome formation. Nat Commun. 2025 Aug 22;16(1):7852. doi: 10.1038/s41467-025-62751-5. PubMed PMID: 40846843; PubMed Central PMCID: PMC12373839.
• Okekenwa S, Tsai M, Dooley P, Wang B, Comassio P, Moreira J, Kriefall N, Martin S, Morfini G, Brady S, Song Y. Divergent Molecular Pathways for Toxicity of Selected Mutant C9ORF72-derived Dipeptide Repeats. bioRxiv. 2024 Jun 17;. doi: 10.1101/2023.09.28.558663. PubMed PMID: 37808871; PubMed Central PMCID: PMC10557653.
• Brady ST, Mesnard-Hoaglin NA, Mays S, Priego M, Dziechciowska J, Morris S, Kang M, Tsai MY, Purks JL, Klein A, Gaona A, Melloni A, Connors T, Hyman B, Song Y, Morfini GA. Toxic effects of mutant huntingtin in axons are mediated by its proline-rich domain. Brain. 2024 Jun 3;147(6):2098-2113. doi: 10.1093/brain/awad280. PubMed PMID: 37633260; PubMed Central PMCID: PMC11146425.
• Cooper JM, Lathuiliere A, Su EJ, Song Y, Torrente D, Jo Y, Weinrich N, Sales JD, Migliorini M, Sisson TH, Lawrence DA, Hyman BT, Strickland DK. SORL1 is a receptor for tau that promotes tau seeding. J Biol Chem. 2024 Jun;300(6):107313. doi: 10.1016/j.jbc.2024.107313. Epub 2024 Apr 23. PubMed PMID: 38657864; PubMed Central PMCID: PMC11145553.
• Brill MS, Fassier C, Song Y. Editorial: Cytoskeletal alterations in aging and disease. Front Cell Dev Biol. 2023;11:1359465. doi: 10.3389/fcell.2023.1359465. eCollection 2023. PubMed PMID: 38299006; PubMed Central PMCID: PMC10828968.
• König S, Schmidt N, Bechberger K, Morris S, Priego M, Zaky H, Song Y, Pielage J, Brunholz S, Brady ST, Kins S, Morfini G. Axon-Autonomous Effects of the Amyloid Precursor Protein Intracellular Domain (AICD) on Kinase Signaling and Fast Axonal Transport. Cells. 2023 Oct 4;12(19). doi: 10.3390/cells12192403. PubMed PMID: 37830617; PubMed Central PMCID: PMC10572015.
• Zhou M, Fang R, Colson L, Donovan KA, Hunkeler M, Song Y, Zhang C, Chen S, Lee DH, Bradshaw GA, Eisert R, Ye Y, Kalocsay M, Goldberg A, Fischer ES, Lu Y. HUWE1 Amplifies Ubiquitin Modifications to Broadly Stimulate Clearance of Proteins and Aggregates. bioRxiv. 2023 May 30;. doi: 10.1101/2023.05.30.542866. PubMed PMID: 37398461; PubMed Central PMCID: PMC10312588.
• Georgescauld F, Song Y, Dautant A. Structure, Folding and Stability of Nucleoside Diphosphate Kinases. Int J Mol Sci. 2020 Sep 16;21(18). doi: 10.3390/ijms21186779. Review. PubMed PMID: 32947863; PubMed Central PMCID: PMC7554756.
• Song Y. Synaptic Actions of Amyotrophic Lateral Sclerosis-Associated G85R-SOD1 in the Squid Giant Synapse. eNeuro. 2020 Mar/Apr;7(2). doi: 10.1523/ENEURO.0369-19.2020. Print 2020 Mar/Apr. PubMed PMID: 32188708; PubMed Central PMCID: PMC7177748.

Open Positions

• Postdoctoral Fellow
• Technician
• PhD Student