Early nuclear phenotypes and reactive transformation in human iPSC-derived astrocytes from ALS patients withSOD1mutations

Abstract

AbstractAmyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by the progressive death of motor neurons (MNs). MN degeneration in ALS involves both cell-autonomous and non-cell autonomous mechanisms, with glial cells playing important roles in the latter. More specifically, astrocytes with mutations in the ALS-associated geneCu/Zn superoxide dismutase 1(SOD1) promote MN death. The mechanisms by whichSOD1-mutated astrocytes reduce MN survival are incompletely understood. In order to characterize the impact ofSOD1mutations on astrocyte physiology, we generated astrocytes from human induced pluripotent stem cell (iPSC) derived from ALS patients carryingSOD1mutations, together with control isogenic iPSCs. We report that astrocytes harbouringSOD1(A4V) andSOD1(D90A) mutations exhibit molecular and morphological changes indicative of reactive astrogliosis when compared to matching isogenic astrocytes. We show further that a number of nuclear phenotypes precede, or coincide with, reactive transformation. These include increased nuclear oxidative stress and DNA damage, and accumulation of the SOD1 protein in the nucleus. These findings reveal early cell-autonomous phenotypes inSOD1-mutated astrocytes that may contribute to the acquisition of a reactive phenotype involved in alterations of astrocyte-MN communication in ALS.