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PML targets and resolves structured protein inclusions to mitigate neurodegeneration
Yang Wang1, Jia-Xin Zhu2, Fei-Xia Zhan3,4
1State Key Laboratory of Genetics and Development of Complex Phenotypes, Department of Cell and Developmental Biology at School of Life Sciences, Institute of Metabolism and Integrative Biology, Zhongshan Hospital, Fudan University, Shanghai, China. w_yang@fudan.edu.cn.
Nature Cell Biology
|February 25, 2026
Summary
Polyglycine inclusions in neuronal intranuclear inclusion disease disrupt nuclear functions. Promyelocytic leukaemia protein (PML) clears these aggregates, offering a therapeutic strategy for neurodegenerative diseases.
Area of Science:
- Neurobiology
- Molecular Biology
- Genetics
Background:
- Intranuclear inclusions are hallmarks of neurodegenerative diseases, but their formation and function are unclear.
- Polyglycine (polyG) inclusions in neuronal intranuclear inclusion disease (NIID) are poorly understood.
- The role of protein aggregation in neurodegenerative disease pathogenesis requires further investigation.
Purpose of the Study:
- To investigate the assembly mechanisms and pathological roles of polyG inclusions in NIID.
- To identify factors involved in the clearance of intranuclear inclusions.
- To explore the therapeutic potential of targeting protein aggregation in neurodegenerative diseases.
Main Methods:
- Investigated polyG inclusion formation and effects on nuclear functions in NIID models.
- Utilized protein biochemistry and cell biology techniques to study inclusion assembly.
- Employed mouse models of NIID and TDP-43 proteinopathy for in vivo validation.
Main Results:
- Polyglycine inclusions recruit intrinsically disordered proteins, forming immobile condensates that impair nuclear protein quality control and DNA repair.
- Promyelocytic leukaemia protein (PML) actively recognizes and eliminates polyG inclusions via chaperone-mediated disaggregation and proteasome-dependent degradation.
- Engineered PML variants cleared various nuclear and cytoplasmic aggregates (polyG, polyGA, polyQ, TDP-43, SOD1) in vitro and in vivo, alleviating disease phenotypes in mouse models.
Conclusions:
- Nuclear inclusions exhibit conserved spatial organization.
- PML acts as a crucial effector for the clearance of intranuclear protein aggregates.
- PML represents a promising therapeutic target for neurodegenerative diseases characterized by protein aggregation.
