Mechanistic Insights of Astrocyte-Mediated Hyperactive Autophagy and Loss of Motor Neuron Function in SOD1(L39R)Linked Amyotrophic Lateral Sclerosis

Author(s)

Rajpurohit, Chetan Singh ; Kumar, Vivek ; Cheffer, Arquimedes ; Oliveira, Danyllo ; Ulrich, Henning ; Okamoto, Oswaldo Keith ; Zatz, Mayana ; Ansari, Uzair Ahmad ; Khanna, Vinay Kumar ; Pant, Aditya Bhushan

• Document type: Journal article
• Source: Molecular Neurobiology; v. 57, n. 10, p. 17-pg., 2020-07-16.

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with no cure. The reports showed the role of nearby astrocytes around the motor neurons as one among the causes of the disease. However, the exact mechanistic insights are not explored so far. Thus, in the present investigations, we employed the induced pluripotent stem cells (iPSCs) of Cu/Zn-SOD1(L39R)linked ALS patient to convert them into the motor neurons (MNs) and astrocytes. We report that the higher expression of stress granule (SG) marker protein G3BP1, and its co-localization with the mutated Cu/Zn-SOD1(L39R)protein in patient's MNs and astrocytes are linked with AIF1-mediated upregulation of caspase 3/7 and hyper activated autophagy. We also observe the astrocyte-mediated non-cell autonomous neurotoxicity on MNs in ALS. The secretome of the patient's iPSC-derived astrocytes exerts significant oxidative stress in MNs. The findings suggest the hyperactive status of autophagy in MNs, as witnessed by the co-distribution of LAMP1, P62 and LC3 I/II with the autolysosomes. Conversely, the secretome of normal astrocytes has shown neuroprotection in patient's iPSC-derived MNs. The whole-cell patch-clamp assay confirms our findings at a physiological functional level in MNs. Perhaps for the first time, we are reporting that the MN degeneration in ALS triggered by the hyper-activation of autophagy and induced apoptosis in both cell-autonomous and non-cell autonomous conditions. (AU)

• FAPESP's process: 13/08028-1 - CEGH-CEL - Human Genome and Stem Cell Research Center
• Grantee: Mayana Zatz
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 12/50880-4 - Stem cells: from basic studies of kinin and purinergic receptor roles towards therapeutical applications
• Grantee: Alexander Henning Ulrich
• Support Opportunities: Research Projects - Thematic Grants