PolyGA targets the ER stress-adaptive response by impairing GRP75 function at the MAM in C9ORF72-ALS/FTD
Acta Neuropathologica, vol. 144, pp. 939–966
Abstract
Abstract ER stress signaling is linked to the pathophysiological and clinical disease manifestations in amyotrophic lateral sclerosis (ALS). Here, we have investigated ER stress-induced adaptive mechanisms in C9ORF72 -ALS/FTD, focusing on uncovering early endogenous neuroprotective mechanisms and the crosstalk between pathological and adaptive responses in disease onset and progression. We provide evidence for the early onset of ER stress-mediated adaptive response in C9ORF72 patient-derived motoneurons (MNs), reflected by the elevated increase in GRP75 expression. These transiently increased GRP75 levels enhance ER–mitochondrial association, boosting mitochondrial function and sustaining cellular bioenergetics during the initial stage of disease, thereby counteracting early mitochondrial deficits. In C9orf72 rodent neurons, an abrupt reduction in GRP75 expression coincided with the onset of UPR, mitochondrial dysfunction and the emergence of PolyGA aggregates, which co-localize with GRP75. Similarly, the overexpression of PolyGA in WT cortical neurons or C9ORF72 patient-derived MNs led to the sequestration of GRP75 within PolyGA inclusions, resulting in mitochondrial calcium (Ca 2+ ) uptake impairments. Corroborating these findings, we found that PolyGA aggregate-bearing human post-mortem C9ORF72 hippocampal dentate gyrus neurons not only display reduced expression of GRP75 but also exhibit GRP75 sequestration within inclusions. Sustaining high GRP75 expression in spinal C9orf72 rodent MNs specifically prevented ER stress, normalized mitochondrial function, abrogated PolyGA accumulation in spinal MNs, and ameliorated ALS-associated behavioral phenotype. Taken together, our results are in line with the notion that neurons in C9ORF72 -ALS/FTD are particularly susceptible to ER–mitochondrial dysfunction and that GRP75 serves as a critical endogenous neuroprotective factor. This neuroprotective pathway, is eventually targeted by PolyGA, leading to GRP75 sequestration, and its subsequent loss of function at the MAM, compromising mitochondrial function and promoting disease onset.
Authors 22
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University of Bern · University Hospital of Bern
Affiliation as printed
Department for BioMedical Research, University of Bern, Bern, Switzerland
Department of Neurology, Inselspital, University Hospital, Bern, Switzerland
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University of Bern · University Hospital of Bern
Affiliation as printed
Department for BioMedical Research, University of Bern, Bern, Switzerland
Department of Neurology, Inselspital, University Hospital, Bern, Switzerland
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University of Bern · University Hospital of Bern
Affiliation as printed
Department for BioMedical Research, University of Bern, Bern, Switzerland
Department of Neurology, Inselspital, University Hospital, Bern, Switzerland
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Affiliation as printed
Institute of Anatomy, University of Bern, Bern, Switzerland
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Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Institute of Neuropathology, RWTH Aachen University Hospital, Aachen, Germany
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Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Institute of Neuropathology, RWTH Aachen University Hospital, Aachen, Germany
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Affiliation as printed
Department of Neurology, Inselspital, University Hospital, Bern, Switzerland
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University of Bern · University Hospital of Bern
Affiliation as printed
Department for BioMedical Research, University of Bern, Bern, Switzerland
Department of Neurology, Inselspital, University Hospital, Bern, Switzerland
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Nationwide Children's Hospital
Affiliation as printed
Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA
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Nationwide Children's Hospital
Affiliation as printed
Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA
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Affiliation as printed
Department of Neurology and Biological Chemistry and Pharmacology, The Ohio State University, Columbus, OH, USA
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Amsterdam Neuroscience · Amsterdam University Medical Centers · University of Amsterdam
Affiliation as printed
Department of (Neuro) Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Amsterdam, The Netherlands
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Affiliation as printed
Department of Neurosurgery, Inselspital, University Hospital, Bern, Switzerland
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Affiliation as printed
Department of Neurosurgery, Inselspital, University Hospital, Bern, Switzerland
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Centre National de la Recherche Scientifique · Inserm · Institut de génétique et de biologie moléculaire et cellulaire · Université de Strasbourg
Affiliation as printed
CNRS, Inserm, IGBMC UMR 7104, U 1258, Université de Strasbourg, F-67404, Illkirch, France
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UK Dementia Research Institute · Euan MacDonald Centre for Motor Neuron Disease Research · University of Edinburgh
Affiliation as printed
Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, EH16 4SB, UK
Euan MacDonald Centre for MND Research, University of Edinburgh, Edinburgh, EH16 4SB, UK
UK Dementia Research Institute at University of Edinburgh, University of Edinburgh, Edinburgh, EH16 4SB, UK
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UK Dementia Research Institute · Euan MacDonald Centre for Motor Neuron Disease Research · University of Edinburgh
Affiliation as printed
Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, EH16 4SB, UK
Euan MacDonald Centre for MND Research, University of Edinburgh, Edinburgh, EH16 4SB, UK
UK Dementia Research Institute at University of Edinburgh, University of Edinburgh, Edinburgh, EH16 4SB, UK
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Nationwide Children's Hospital · The Ohio State University
Affiliation as printed
Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA
Department of Pediatrics, The Ohio State University, Columbus, OH, USA
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Affiliation as printed
Institute of Anatomy, University of Bern, Bern, Switzerland
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Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Institute of Neuropathology, RWTH Aachen University Hospital, Aachen, Germany
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Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Institute of Neuropathology, RWTH Aachen University Hospital, Aachen, Germany
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Smita Saxena corresponding
University of Bern · University Hospital of Bern
Affiliation as printed
Department for BioMedical Research, University of Bern, Bern, Switzerland. smita.saxena@dbmr.unibe.ch
Department of Neurology, Inselspital, University Hospital, Bern, Switzerland. smita.saxena@dbmr.unibe.ch
Department for BioMedical Research, University of Bern, Bern, Switzerland
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