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Upstream open reading frame with NOTCH2NLC GGC expansion generates polyglycine aggregates and disrupts nucleocytoplasmic transport: implications for polyglycine diseases

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Abstract

Neuronal intranuclear inclusion disease (NIID) is neurodegenerative disease characterized by widespread inclusions. Despite the identification of GGC repeat expansion in 5’UTR of NOTCH2NLC gene in adult-onset NIIDs, its pathogenic mechanism remains unclear. Gain-of-function poly-amino-acid proteins generated by unconventional translation have been revealed in nucleotide repeat expansion disorders, inspiring us to explore the possibility of unconventional translation in NIID. Here we demonstrated that NOTCH2NLC 5’UTR triggers the translation of a polyglycine (polyG)-containing protein, N2NLCpolyG. N2NLCpolyG accumulates in p62-positive inclusions in cultured cells, mouse models, and NIID patient tissues with NOTCH2NLC GGC expansion. Translation of N2NLCpolyG is initiated by an upstream open reading frame (uORF) embedding the GGC repeats. N2NLCpolyG tends to aggregate with the increase of GGC repeat units, and displays phase separation properties. N2NLCpolyG aggregation impairs nuclear lamina and nucleocytoplasmic transport but does not necessarily cause acute death on neuronal cells. Our study suggests a similarity of pathogenic mechanisms between NIID and another GGC-repeat disease, fragile X-associated tremor ataxia syndrome. These findings expand our knowledge of protein gain-of-function in NIID, and further highlight evidence for a novel spectrum of diseases caused by aberrant polyG protein aggregation, namely the polyG diseases.

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Abbreviations

5’UTR:

5’-Untranslated regions

ADLD:

Adult-onset autosomal-dominant leukodystrophy

CDS:

Coding sequence

FXTAS:

Fragile X-associated tremor/ataxia syndrome

GFP:

Green fluorescence protein

IUE:

In-utero electroporation

NIID:

Neuronal intranuclear inclusion disease

LLPS:

Liquid-to-liquid phase separation

NREDs:

Nucleotide repeat expansion disorders

polyA RNA:

Polyadenylated RNA

polyG:

Polyglycine

RAN:

Repeat-associated non-AUG

ribo-seq:

Ribosome profiling

uORF:

Upstream open reading frame

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Acknowledgements

This work was supported by project grants from the National Natural Science Foundation of China (Code: 81771308, 31771184). We thank the patients and control subjects for participating in the study. We also thank the neurologists, pathologists and radiologists for their help in collecting clinical information, especially Dr. Yang Cai, Dr. ** Zhong, Yangye Lian, Wenyi Luo, **-Zhong-Aff1">Shao** Zhong

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    Zhong, S., Lian, Y., Luo, W. et al. Upstream open reading frame with NOTCH2NLC GGC expansion generates polyglycine aggregates and disrupts nucleocytoplasmic transport: implications for polyglycine diseases. Acta Neuropathol 142, 1003–1023 (2021). https://doi.org/10.1007/s00401-021-02375-3

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