Inactivation of Hippo and cJun-N-terminal Kinase (JNK) signaling mitigate FUS mediated neurodegeneration in-vivo

Author(s)

Ankita Sarkar, University of DaytonFollow
Abijeet Singh Mehta, University of DaytonFollow
Prajakta Deshpande, University of DaytonFollow
Madhuri Kango-Singh, University of DaytonFollow
Udai Bhan Pandey, University of Pittsburgh
Amit Singh (0000-0002-2962-2255), University of DaytonFollow

Document Type

Article

Publication Date

7-2020

Publication Source

Neurobiology of Disease

Abstract

Amyotrophic Lateral Sclerosis (ALS), a late-onset neurodegenerative disorder characterized by the loss of motor neurons in the central nervous system, has no known cure to-date. Disease causing mutations in human Fused in Sarcoma (FUS) leads to aggressive and juvenile onset of ALS. FUS is a well-conserved protein across different species, which plays a crucial role in regulating different aspects of RNA metabolism. Targeted misexpression of FUS in Drosophila model recapitulates several interesting phenotypes relevant to ALS including cytoplasmic mislocalization, defects at the neuromuscular junction and motor dysfunction. We screened for the genetic modifiers of human FUS-mediated neurodegenerative phenotype using molecularly defined deficiencies. We identified hippo (hpo), a component of the evolutionarily conserved Hippo growth regulatory pathway, as a genetic modifier of FUS mediated neurodegeneration. Gain-of-function of hpotriggers cell death whereas its loss-of-function promotes cell proliferation. Downregulation of the Hippo signaling pathway, using mutants of Hippo signaling, exhibit rescue of FUS-mediated neurodegeneration in the Drosophila eye, as evident from reduction in the number of TUNEL positive nuclei as well as rescue of axonal targeting from the retina to the brain. The Hippo pathway activates c-Jun amino-terminal (NH2) Kinase (JNK) mediated cell death. We found that downregulation of JNK signaling is sufficient to rescue FUS-mediated neurodegeneration in the Drosophila eye. Our study elucidates that Hippo signaling and JNK signaling are activated in response to FUS accumulation to induce neurodegeneration. These studies will shed light on the genetic mechanism involved in neurodegeneration observed in ALS and other associated disorders.

ISBN/ISSN

0969-9961

Document Version

Published Version

Comments

Content is licensed as open access under the Creative Commons license CC-BY-NC-ND (Attribution-NonCommercial-NoDerivatives 4.0 International)

Publisher

Elsevier

Volume

140

Peer Reviewed

yes

Keywords

Neurodegeneration, Amyotrophic Lateral Sclerosis (ALS), Fused in Sarcoma (FUS), Translocated in Liposarcoma (TLS), Drosophila eye, Hippo pathway, JNK signaling, Cell death

eCommons Citation

Sarkar, Ankita; Mehta, Abijeet Singh; Deshpande, Prajakta; Kango-Singh, Madhuri; Pandey, Udai Bhan; and Singh, Amit, "Inactivation of Hippo and cJun-N-terminal Kinase (JNK) signaling mitigate FUS mediated neurodegeneration in-vivo" (2020). Biology Faculty Publications. 257.
https://ecommons.udayton.edu/bio_fac_pub/257