The TNKS/PI31–proteasome axis as a central node in TDP-43 neuropathies
9 affiliations
- 1Ph.D. Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Shuang-Ho Campus, New Taipei City, 235 Taiwan
- 2TMU Research Center of Neuroscience, Taipei Medical University, Taipei, 110 Taiwan
- 3Department of Biology, Georgetown University, Washington, DC 20057 United States
- 4International Master Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University, Shuang-Ho Campus, New Taipei City, 235 Taiwan
- 5Institute of Molecular Biology, Academia Sinica, Taipei, 115 Taiwan
- 6Department of Neurology, Shuang-Ho Hospital, Taipei Medical University, New Taipei City, 235 Taiwan
- 7Taipei Neuroscience Institute, Taipei Medical University, New Taipei City, 235 Taiwan
- 8Department of Neurology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 110 Taiwan
- 9School of Medicine, College of Medicine, Taipei Medical University, Taipei, 110 Taiwan
Abstract
Background: Pathological aggregation of Tar DNA-binding protein 43 (TDP-43) and disruption of neuronal protein homeostasis are defining features of amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and related TDP-43 proteinopathies. Efficient axonal transport of proteasomes is essential for maintaining local protein quality control in neurons. Proteasome inhibitor 31 (PI31) regulates both 26S proteasome assembly and dynein-mediated transport of 20S proteasomes. Although Tankyrase 1/2 (TNKS)-mediated ADP-ribosylation of PI31 promotes 26S proteasome assembly, its role in proteasome transport and its contribution to TDP-43 pathology remain unclear.
Methods: Live-cell imaging was performed to examine 20S proteasome transport in primary cortical and motor neurons from wild-type and Prp-TDP-43A315T transgenic mice. Protein interactions among TDP-43, TNKS, and PI31 were analyzed by immunoprecipitation and Förster resonance energy transfer (FRET). Insoluble protein accumulation and colocalization were assessed by RIPA/urea fractionation, Western blotting, and immunofluorescence. Proteasome assembly and activity were evaluated using native gel electrophoresis and a 20S proteasome-specific fluorogenic substrate. TDP-43 aggregation was examined by semi-denaturing detergent agarose gel electrophoresis (SDD-AGE).
Results: In cell models expressing TDP-43-FL, TDP-43-A315T, or TDP-25 and in Prp-TDP-43A315T transgenic mice, pathological TDP-43 species formed distinct aggregates, ranging from oligomers to prominent cytoplasmic aggregates, yet all reduced proteasome activity, impaired axonal proteasome transport, and caused the accumulation of polyubiquitinated proteins, PI31, 20S proteasomes, and TDP-43 in the proximal axon and cell body. Pathological TDP-43 sequestered TNKS and proteasome components into insoluble fractions, thereby limiting the availability of free and soluble TNKS for interaction with PI31 and subsequent PI31 ADP-ribosylation, ultimately impairing 19S/20S proteasome assembly. Notably, disruption of the TNKS–PI31 interaction or inhibition of TNKS activity recapitulated the proteasome dysfunction induced by pathological TDP-43, supporting a role for the aberrant TNKS–TDP-43 interaction and consequent impairment of TNKS-mediated PI31 ADP-ribosylation in TNKS/PI31/proteasome axis dysfunction.
Conclusions: Pathological TDP-43 disrupts proteasome function by impairing the TNKS/PI31/proteasome axis, suggesting that this axis may represent a potential therapeutic target for TDP-43 proteinopathies. Selectively restoring this pathway may enhance pathological TDP-43 clearance while minimizing nonspecific proteasome activation, thereby providing a more precise and safer therapeutic strategy for ALS and FTLD.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12929-026-01296-1.
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BibTeX
@article{bubphachat2026tnkspi31proteasome,
title = {{The TNKS/PI31–proteasome axis as a central node in TDP-43 neuropathies}},
author = {Pitchapa Bubphachat and Pritha Majumder and I.-Fang Wang and Jeffrey K. Huang and Tzu-Jen Kao and Yi-Chao Lee and Che-Kun James Shen and Guan-Chou Chen and Po-Chih Chen and Chi-Chen Sarah Huang},
journal = {Journal of Biomedical Science},
year = {2026},
month = nov,
doi = {10.1186/s12929-026-01296-1},
url = {https://doi.org/10.1186/s12929-026-01296-1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - The TNKS/PI31–proteasome axis as a central node in TDP-43 neuropathies
AU - Pitchapa Bubphachat
AU - Pritha Majumder
AU - I.-Fang Wang
AU - Jeffrey K. Huang
AU - Tzu-Jen Kao
AU - Yi-Chao Lee
AU - Che-Kun James Shen
AU - Guan-Chou Chen
AU - Po-Chih Chen
AU - Chi-Chen Sarah Huang
PY - 2026
DA - 2026/11/04
JO - Journal of Biomedical Science
DO - 10.1186/s12929-026-01296-1
UR - https://doi.org/10.1186/s12929-026-01296-1
AB - Background: Pathological aggregation of Tar DNA-binding protein 43 (TDP-43) and disruption of neuronal protein homeostasis are defining features of amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and related TDP-43 proteinopathies. Efficient axonal transport of proteasomes is essential for maintaining local protein quality control in neurons. Proteasome inhibitor 31 (PI31) regulates both 26S proteasome assembly and dynein-mediated transport of 20S proteasomes. Although Tankyrase 1/2 (TNKS)-mediated ADP-ribosylation of PI31 promotes 26S proteasome assembly, its role in proteasome transport and its contribution to TDP-43 pathology remain unclear. Methods: Live-cell imaging was performed to examine 20S proteasome transport in primary cortical and motor neurons from wild-type and Prp-TDP-43A315T transgenic mice. Protein interactions among TDP-43, TNKS, and PI31 were analyzed by immunoprecipitation and Förster resonance energy transfer (FRET). Insoluble protein accumulation and colocalization were assessed by RIPA/urea fractionation, Western blotting, and immunofluorescence. Proteasome assembly and activity were evaluated using native gel electrophoresis and a 20S proteasome-specific fluorogenic substrate. TDP-43 aggregation was examined by semi-denaturing detergent agarose gel electrophoresis (SDD-AGE). Results: In cell models expressing TDP-43-FL, TDP-43-A315T, or TDP-25 and in Prp-TDP-43A315T transgenic mice, pathological TDP-43 species formed distinct aggregates, ranging from oligomers to prominent cytoplasmic aggregates, yet all reduced proteasome activity, impaired axonal proteasome transport, and caused the accumulation of polyubiquitinated proteins, PI31, 20S proteasomes, and TDP-43 in the proximal axon and cell body. Pathological TDP-43 sequestered TNKS and proteasome components into insoluble fractions, thereby limiting the availability of free and soluble TNKS for interaction with PI31 and subsequent PI31 ADP-ribosylation, ultimately impairing 19S/20S proteasome assembly. Notably, disruption of the TNKS–PI31 interaction or inhibition of TNKS activity recapitulated the proteasome dysfunction induced by pathological TDP-43, supporting a role for the aberrant TNKS–TDP-43 interaction and consequent impairment of TNKS-mediated PI31 ADP-ribosylation in TNKS/PI31/proteasome axis dysfunction. Conclusions: Pathological TDP-43 disrupts proteasome function by impairing the TNKS/PI31/proteasome axis, suggesting that this axis may represent a potential therapeutic target for TDP-43 proteinopathies. Selectively restoring this pathway may enhance pathological TDP-43 clearance while minimizing nonspecific proteasome activation, thereby providing a more precise and safer therapeutic strategy for ALS and FTLD. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12929-026-01296-1.
SN - 1021-7770
SN - 1423-0127
ER -