Circ-Hdgfrp3 shuttles along neurites and is trapped in aggregates formed by ALS-associated mutant FUS

Eleonora D'Ambra; Tiziana Santini; Erika Vitiello; Sara D'Uva; Valentina Silenzi; Mariangela Morlando; Irene Bozzoni

doi:10.1016/j.isci.2021.103504

Circ-Hdgfrp3 shuttles along neurites and is trapped in aggregates formed by ALS-associated mutant FUS

iScience. 2021 Nov 25;24(12):103504. doi: 10.1016/j.isci.2021.103504. eCollection 2021 Dec 17.

Authors

Eleonora D'Ambra^{1

2}, Tiziana Santini^{1

2}, Erika Vitiello^{1

3}, Sara D'Uva¹, Valentina Silenzi^{1

2}, Mariangela Morlando⁴, Irene Bozzoni^{1

2

3}

Affiliations

¹ Department of Biology and Biotechnology 'Charles Darwin', Sapienza University of Rome, Rome, Italy.
² Center for Life Nano- & Neuro-Science, Fondazione Istituto Italiano di Tecnologia, Rome, Italy.
³ Center for Human Technology@ Istituto Italiano di Tecnologia, Genova, Italy.
⁴ Department of Pharmaceutical Sciences, "Department of Excellence 2018-2022", University of Perugia, Perugia, Italy.

Abstract

CircRNAs belong to a family of RNA molecules which are conserved in evolution, have tissue-specific expression, and are abundant in neuronal cells. Here, we define several features of circ-Hdgfrp3 and describe interesting alterations occurring in motor neurons (MNs) carrying ALS-associated FUS mutations. Through a highly sensitive in situ approach we describe that circ-Hdgfrp3 traffics along neurites, while upon oxidative stress it is retained in the perinuclear region. While in wild-type stressed MNs, circ-Hdgfrp3 localizes in stress granules (SGs), in MNs carrying mutant FUS, a higher proportion of circ-Hdgfrp3 was trapped into cytoplasmic aggregates. Upon stress removal, circ-Hdgfrp3 was easily freed from SGs whereas it was less efficiently released from FUS-aggregates. We found that the human circ-Hdgfrp3 counterpart was also similarly associated to mutant FUS-aggregates in stressed neuronal cells. Overall, the alteration of circ-Hdgfrp3 trafficking adds a further layer of complexity to the role of FUS-aggregates in ALS disease.

Keywords: Biological sciences; Cellular neuroscience; Molecular neuroscience.