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

NEUROBIOLOGY OF DISEASE

卷:140

Review

Gogia, Neha¹  Sarkar, Ankita¹  Mehta, Abijeet Singh¹  Ramesh, Nandini²  Deshpande, Prajakta¹  Kango-Singh, Madhuri^1,3,4  Pandey, Udai Bhan²  Singh, Amit^1,3,4,5,6 

[1] Univ Dayton, Dept Biol, Dayton, OH 45469 USA

[2] Univ Pittsburgh, Dept Pediat, Childrens Hosp Pittsburgh, Sch Med, Pittsburgh, PA 15260 USA

[3] Univ Dayton, Premed Program, Dayton, OH 45469 USA

[4] Univ Dayton, Ctr Tissue Regenerat & Engn Dayton TREND, Dayton, OH 45469 USA

[5] Univ Dayton, Integrat Sci & Engn Ctr, Dayton, OH 45469 USA

[6] Indiana State Univ, Ctr Genom Advocacy TCGA, Terre Haute, IN 47809 USA

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

DOI  :  10.1016/j.nbd.2020.104837

来源: Elsevier

【 摘 要 】

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 hpo triggers 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 (NH 2 ) 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.