Cryo-EM advances in TDP-43 amyloid fibrils structure determination

TAR DNA-binding protein 43 (TDP-43) is a DNA/RNA-binding protein whose pathological aggregation characterizes a spectrum of neurodegenerative disorders known as TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and chronic traumatic encephalopathy (CTE). Recent breakthroughs in cryo-electron microscopy (cryo-EM) have revolutionized our understanding of these diseases by resolving the atomic structures of TDP-43 amyloid fibrils. These structural insights have been pivotal in elucidating the transition from functional liquid-liquid phase separation (LLPS) to irreversible solid-state aggregation. This review synthesizes key cryo-EM findings from 2019 to 2026, encompassing fibrils formed by the full-length low-complexity domain, disease-relevant core fragments, and filaments extracted directly from patient tissues, as well as the pathological implications of distinct structural polymorphs. These findings not only deepen our understanding of the brain science aspects of the pathogenesis of TDP-43 proteinopathies, but also provide an important structural basis for the development of specific conformational diagnostic methods and targeted therapeutic drugs.