Journal Article

Impaired DNA damage response signaling by FUS-NLS mutations leads to neurodegeneration and FUS aggregate formation

Storch, Alexander, Ludolph, Albert C., Petri, Susanne, Holzmann, Karlheinz, Vehlow, Anne, Lojewski, Xenia, Frickenhaus, Marie, Storkebaum, Erik, Pal, Arun, Weis, Joachim, Boeckers, Tobias M., Stanslowsky, Nancy, Hyman, Anthony A., Freischmidt, Axel, Cordes, Nils, Sterneckert, Jared, Naumann, Marcel, Poser, Ina, Troost, Dirk, Grill, Stephan W., Japtok, Julia, Weishaupt, Jochen H., Hermann, Andreas, Pan-Montojo, Francisco, Naujock, Maximilian, Wegner, Florian, Goswami, Anand, Liebau, Stefan, Günther, René, Jin, Mengmeng, Reinhardt, Peter

2018

Overview

Amyotrophic lateral sclerosis (ALS) is the most frequent motor neuron disease. Cytoplasmic fused in sarcoma (FUS) aggregates are pathological hallmarks of FUS-ALS. Proper shuttling between the nucleus and cytoplasm is essential for physiological cell function. However, the initial event in the pathophysiology of FUS-ALS remains enigmatic. Using human induced pluripotent stem cell (hiPSCs)-derived motor neurons (MNs), we show that impairment of poly(ADP-ribose) polymerase (PARP)-dependent DNA damage response (DDR) signaling due to mutations in the FUS nuclear localization sequence (NLS) induces additional cytoplasmic FUS mislocalization which in turn results in neurodegeneration and FUS aggregate formation. Our work suggests that a key pathophysiologic event in ALS is upstream of aggregate formation. Targeting DDR signaling could lead to novel therapeutic routes for ameliorating ALS. Abnormal cytoplasmic aggregates of FUS are a hallmark of some forms of amyotrophic lateral sclerosis (ALS). Here, using neurons derived from patients with FUS-ALS, the authors demonstrate that impairment of PARP-dependent DNA damage signaling is an event that occurs upstream of neurodegeneration and cytoplasmic aggregate formation in FUS-ALS.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/337/1427/2566 / 631/378/1689/1285 / Adenosine diphosphate / Amyotrophic lateral sclerosis / Cytoplasm / Damage localization / Deoxyribonucleic acid / DNA / DNA damage / FUS protein / Humanities and Social Sciences / Localization / Motor neuron diseases / multidisciplinary / Mutation / Neurodegeneration / Neurodegenerative diseases / Nuclei (cytology) / Pathophysiology / Pluripotency / Poly(ADP-ribose) / Poly(ADP-ribose) polymerase / Ribose / Sarcoma / Science / Science (multidisciplinary) / Signaling / Stem cells