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000163726 1001_ $$0P:(DE-2719)2811849$$aGünther, René$$b0$$eFirst author$$udzne
000163726 245__ $$aAlteration of Mitochondrial Integrity as Upstream Event in the Pathophysiology of SOD1-ALS
000163726 260__ $$aBasel$$bMDPI$$c2022
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000163726 520__ $$aLittle 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.
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000163726 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: metabolism
000163726 650_2 $$2MeSH$$aHumans
000163726 650_2 $$2MeSH$$aInduced Pluripotent Stem Cells: metabolism
000163726 650_2 $$2MeSH$$aMitochondria: metabolism
000163726 650_2 $$2MeSH$$aSuperoxide Dismutase-1: genetics
000163726 650_2 $$2MeSH$$aSuperoxide Dismutase-1: metabolism
000163726 7001_ $$0P:(DE-2719)9000245$$aPal, Arun$$b1$$udzne
000163726 7001_ $$aWilliams, Chloe$$b2
000163726 7001_ $$00000-0001-8601-4451$$aZimyanin, Vitaly L.$$b3
000163726 7001_ $$aLiehr, Maria$$b4
000163726 7001_ $$00000-0003-2955-1626$$avon Neubeck, Cläre$$b5
000163726 7001_ $$aKrause, Mechthild$$b6
000163726 7001_ $$aParab, Mrudula G.$$b7
000163726 7001_ $$aPetri, Susanne$$b8
000163726 7001_ $$aKalmbach, Norman$$b9
000163726 7001_ $$aMarklund, Stefan L.$$b10
000163726 7001_ $$00000-0002-7688-3124$$aSterneckert, Jared$$b11
000163726 7001_ $$aMunch Andersen, Peter$$b12
000163726 7001_ $$aWegner, Florian$$b13
000163726 7001_ $$00000-0002-6884-4774$$aGilthorpe, Jonathan D.$$b14
000163726 7001_ $$0P:(DE-2719)2811732$$aHermann, Andreas$$b15$$eLast author$$udzne
000163726 770__ $$aNeurodegenerative and Neurologic Disease: Genes, Mechanisms, and Therapies
000163726 773__ $$0PERI:(DE-600)2661518-6$$a10.3390/cells11071246$$gVol. 11, no. 7, p. 1246 -$$n7$$p1246$$tCells$$v11$$x2073-4409$$y2022
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