Sut-6/NIPP1 modulates tau toxicity

• Published in: Human molecular genetics 2023-07, Vol.32 (14), p.2292-2306
• Main Authors: Kow, R L, Black, A H, Henderson, B P, Kraemer, B C
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Animals; Caenorhabditis elegans - genetics; Caenorhabditis elegans - metabolism; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; Disease Models, Animal; Humans; Original; tau Proteins - genetics; tau Proteins - metabolism; Tauopathies - metabolism
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddad049

Abstract Neurodegenerative diseases exhibiting the pathological accumulation of tau such as Alzheimer’s disease and related disorders still have no disease-modifying treatments and the molecular mechanisms of neurodegeneration remain unclear. To discover additional suppressor of tauopathy (sut) genes that mediate or modulate the toxicity of pathological tau, we performed a classical genetic screen using a tau transgenic Caenorhabditis elegans model. From this screen, we identified the suppressing mutation W292X in sut-6, the C. elegans homolog of human NIPP1, which truncates the C-terminal RNA-binding domain. Using CRISPR-based genome editing approaches, we generated null and additional C-terminally truncated alleles in sut-6 and found that loss of sut-6 or sut-6(W292X) suppresses tau-induced behavioral locomotor deficits, tau protein accumulation and neuron loss. The sut-6(W292X) mutation showed stronger and semi-dominant suppression of tau toxicity while sut-6 deletion acted recessively. Neuronal overexpression of SUT-6 protein did not significantly alter tau toxicity, but neuronal overexpression of SUT-6 W292X mutant protein reduced tau-mediated deficits. Epistasis studies showed tauopathy suppression by sut-6 occurs independent of other known nuclear speckle-localized suppressors of tau such as sut-2, aly-1/aly-3 and spop-1. In summary, we have shown that sut-6/NIPP1 modulates tau toxicity and found a dominant mutation in the RNA-binding domain of sut-6 which strongly suppresses tau toxicity. This suggests that altering RNA-related functions of SUT-6/NIPP1 instead of complete loss of SUT-6/NIPP1 will provide the strongest suppression of tau.