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Audience
Researchers interested in learning more about TAR DNA-binding protein 43 (TDP-43).
Dates
April 9, 2024 | 10 a.m. - 4:10 p.m. ET
April 10, 2024 | 10 a.m. - 3:35 p.m. ET
Purpose and Background
Proteinopathy of TAR DNA-binding protein 43 (TDP-43) is observed in multiple neurodegenerative diseases, including Alzheimer's disease (AD) and limbic predominant age-related TDP-43 encephalopathy (LATE). Understanding the heterotypic TDP-43 proteinopathy will identify novel therapeutic avenues for neurodegenerative diseases. TDP-43 belongs to the heterogenous nuclear ribonucleoprotein (hnRNP) family, which is mainly present in the nucleus and plays important roles in RNA regulation, such as alternative splicing, transcriptional regulation, and mRNA stabilization. Under pathological conditions, various forms of TDP-43 proteinopathy develop, such as loss of normal nuclear TDP-43, protein aggregation in the neuronal cytoplasm, as well as abnormal TDP-43 accumulation in nuclei of neurons, oligodendroglia, and astrocytes. This workshop of leaders and innovators in the field was timely to fill in the gaps in our understanding of mislocalization and dysfunction of TDP-43. In addition, it addressed the mechanisms of TDP-43 aggregation and propagation in LATE and AD. Outcomes from this workshop identified the critical events for maintenance of TDP-43 functions and brain health.
Agenda
Note: All times listed below are Eastern Daylight Time.
Day 1 (Tuesday, April 9)
10:00 a.m. Welcome Remarks, Eliezer Masliah, National Institute on Aging (NIA)
10:10 a.m. Workshop Objectives, Tong Li and Lisa Opanashuk, NIA
10:20 a.m. Keynote: Clinical and Biological Heterogeneity of TDP-43 Disorders, David Irwin, University of Pennsylvania
10:50 a.m. Break
Session 1 | Pathology and Etiology of LATE and AD. Chair: Julie Schneider, Rush University
11:00 a.m. Pathology and pathways to cognitive decline: the role of TDP-43 and neurofibrillary tangles in AD and LATE? Julie Schneider, Rush University
11:20 a.m. Genetic and clinical-pathological link between AD and LATE, Hyun-Sik Yang, Harvard Medical School and Brigham and Women's Hospital
11:40 a.m. TMEM106B pathology in LATE-NC, Ian Mackenzie, University of British Columbia and Vancouver General Hospital
12:00 p.m. Q&A/moderated discussion
12:30 p.m. Lunch
Session 2 | Molecular Mechanisms of TDP-43, Loss of Nuclear Function With or Without Protein Aggregation Chair: Philip Wong, Johns Hopkins University
1:00 p.m. How does loss of TDP-43 function contribute to accelerated neurodegeneration in AD with co-pathology of TDP-43?, Philip Wong, Johns Hopkins University
1:20 p.m. TDP-43 nuclear loss in FTD/ALS causes widespread alternative polyadenylation changes, Aaron Gitler, Stanford University
1:40 p.m. Identifying and therapeutically targeting splicing alterations in TDP-43 proteinopathies, Clotilde Lagier-Tourenne, Massachusetts General Hospital and Harvard Medical School
2:00 p.m. Q&A/moderated discussion
2:30 p.m. Break
Session 3 | Regulation of TDP-43 Pathologies in AD and LATE. Chair: Yuna Ayala, Saint Louis University
2:40 p.m. Role of RNA-mediated condensation in regulating TDP-43 function and homeostasis, Yuna Ayala, Saint Louis University
3:00 p.m. Regulation of amyloid deposition by TDP-43 liquid-liquid phase separation, Xinglong Wang, University of Arizona
3:20 p.m. Prion mechanisms for TDP-43: New tools and concepts, Marc Diamond, UT Southwestern Medical Center
3:40 p.m. Q&A/moderated discussion
4:10 p.m. Adjourn Day 1
Day 2 (Wednesday, April 10)
10:00 a.m. Welcome, NIA Staff
Session 4 | Clinical and Genetic Feature of LATE and AD as Compared to Other TDP-43 Diseases Chair: Tamar Gefen, Northwestern University
10:05 a.m. TDP-43 in cognitive Superagers, Tamar Gefen, Northwestern University
10:25 a.m. Clinical and neuroimaging features of LATE: A framework for clinical diagnosis, David Wolk, University of Pennsylvania
10:45 a.m. Harnessing the power of iPSC models to uncover mechanisms of TDP-43 pathobiology, Michael Ward, National Institute of Neurological Disorders and Stroke (NINDS)
11:05 a.m. Q&A/moderated discussion
11:35 a.m. Lunch
Session 5 | Nuclear Import and Export of TDP-43 Chair: Wilfried Rossoll, Mayo Clinic
12:10 p.m. TDP-43 nucleocytoplasmic transport: mechanisms and regulation by RNA, Lindsey Hayes, The Johns Hopkins University School of Medicine
12:30 p.m. Nuclear transport factors as regulators of TDP-43 pathology, Wilfried Rossoll, Mayo Clinic, Florida
12:50 p.m. TAR DNA binding protein-43 KDa (TDP-43) pathology causes differential expression of retrotransposons in the TDP-43-WT and TDP-43-Q331K mouse models,Roger Sher, Stony Brook University
1:10 p.m. Q&A/moderated discussion
1:40 p.m. Break
Session 6 | Mini Session: Structures of TDP-43
1:50 p.m. Structures of TDP-43 filaments from human neurodegenerative diseases, Diana Arseni, MRC Laboratory of Molecular Biology, Cambridge
2:15 p.m. Synthesis by Moderators
3:15 p.m. Final discussion and Closing Remarks, Lisa Opanashuk and Tong Li, NIA
3:35 p.m. Adjourn Day 2
Contact Information
Please contact Dr. Tong Li ( tong.li3@nih.gov ) and Dr. Lisa Opanashuk ( lisa.opanashuk@nih.gov ) with any questions about the workshop.