TY  - JOUR
AU  - Günther, René
AU  - Pal, Arun
AU  - Williams, Chloe
AU  - Zimyanin, Vitaly L.
AU  - Liehr, Maria
AU  - von Neubeck, Cläre
AU  - Krause, Mechthild
AU  - Parab, Mrudula G.
AU  - Petri, Susanne
AU  - Kalmbach, Norman
AU  - Marklund, Stefan L.
AU  - Sterneckert, Jared
AU  - Munch Andersen, Peter
AU  - Wegner, Florian
AU  - Gilthorpe, Jonathan D.
AU  - Hermann, Andreas
TI  - Alteration of Mitochondrial Integrity as Upstream Event in the Pathophysiology of SOD1-ALS
JO  - Cells
VL  - 11
IS  - 7
SN  - 2073-4409
CY  - Basel
PB  - MDPI
M1  - DZNE-2022-00465
SP  - 1246
PY  - 2022
AB  - Little is known about the early pathogenic events by which mutant superoxide dismutase 1 (SOD1) causes amyotrophic lateral sclerosis (ALS). This lack of mechanistic understanding is a major barrier to the development and evaluation of efficient therapies. Although protein aggregation is known to be involved, it is not understood how mutant SOD1 causes degeneration of motoneurons (MNs). Previous research has relied heavily on the overexpression of mutant SOD1, but the clinical relevance of SOD1 overexpression models remains questionable. We used a human induced pluripotent stem cell (iPSC) model of spinal MNs and three different endogenous ALS-associated SOD1 mutations (D90Ahom, R115Ghet or A4Vhet) to investigate early cellular disturbances in MNs. Although enhanced misfolding and aggregation of SOD1 was induced by proteasome inhibition, it was not affected by activation of the stress granule pathway. Interestingly, we identified loss of mitochondrial, but not lysosomal, integrity as the earliest common pathological phenotype, which preceded elevated levels of insoluble, aggregated SOD1. A super-elongated mitochondrial morphology with impaired inner mitochondrial membrane potential was a unifying feature in mutant SOD1 iPSC-derived MNs. Impaired mitochondrial integrity was most prominent in mutant D90Ahom MNs, whereas both soluble disordered and detergent-resistant misfolded SOD1 was more prominent in R115Ghet and A4Vhet mutant lines. Taking advantage of patient-specific models of SOD1-ALS in vitro, our data suggest that mitochondrial dysfunction is one of the first crucial steps in the pathogenic cascade that leads to SOD1-ALS and also highlights the need for individualized medical approaches for SOD1-ALS.
KW  - Amyotrophic Lateral Sclerosis: metabolism
KW  - Humans
KW  - Induced Pluripotent Stem Cells: metabolism
KW  - Mitochondria: metabolism
KW  - Superoxide Dismutase-1: genetics
KW  - Superoxide Dismutase-1: metabolism
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC8997900
C6  - pmid:35406813
DO  - DOI:10.3390/cells11071246
UR  - https://pub.dzne.de/record/163726
ER  -