FUS Is Not Mislocalized in Spinal Motor Neurons Derived From Human Induced Pluripotent Stem Cells of Main Non-FUS ALS Subtypes

Szewczyk, Barbara; Günther, René; Sterneckert, Jared; Petri, Susanne; Wegner, Florian; Hermann, Andreas

doi:10.1093/jnen/nlaa154

Cited by 2 publications

(2 citation statements)

References 13 publications

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“…ALS-causing mutations in FUS are mainly localized in its NLS and thus causing a cytoplasmic mislocalization, i.e. aggregation (Japtok et al, 2015, Szewczyk et al, 2023, Szewczyk et al, 2021). This is accompanied by a loss of nuclear FUS function including a lack of proper recruitment of FUS to DNA damage sites and DNA damage repair (DDR) (Naumann et al, 2018, Wang et al, 2018).…”

Section: Resultsmentioning

confidence: 99%

“…Most importantly, restoration of mitochondrial inner membrane potential delayed neurodegeneration in FUS-ALS (Naumann et al, 2018). ALS-causing mutations in FUS are mainly localized in its nuclear localization sequence (NLS) and thus causing a cytoplasmic mislocalization (Japtok, Lojewski et al, 2015, Szewczyk, Gunther et al, 2023, Szewczyk, Gunther et al, 2021. This is accompanied by a loss of nuclear FUS function including a lack of proper recruitment of FUS to DNA damage sites and DNA damage repair (DDR) (Naumann et al, 2018, Wang, Guo et al, 2018, a mechanism downstream of poly(ADPribose) polymerase 1 (PARP1) (Mastrocola, Kim et al, 2013, Rulten, Rotheray et al, 2014.…”

Section: Introductionmentioning

confidence: 99%

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DJ-1 products glycolic acid and D-lactate restore deficient axonal trafficking and DNA damage response in FUS and SOD1-associated amyotrophic lateral sclerosis

Pal,

Grossmann,

Glaß

et al. 2023

Preprint

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Amyotrophic Lateral Sclerosis (ALS) is the most common motor neuron disease leading to death within 2-5 years. Currently available drugs can only slightly prolong survival. Despite the progress that has been achieved in unravelling the molecular mechanisms of the disease so far, the underlying pathophysiology is not fully understood. We present novel insights into the pathophysiology of Superoxide Dismutase 1 (SOD1)- and in particular Fused In Sarcoma (FUS)-ALS by revealing a putatively central role of the Parkinsons disease (PD) associated glyoxylase DJ-1 and its products glycolic acid (GA) and D-lactic acid (DL). Combined, but not single, treatment with GA and DL restored axonal trafficking deficits of mitochondria and lysosomes in FUS- and SOD1-ALS patient-derived motoneurons (MNs). This was accompanied by restoration of mitochondrial membrane potential as well as mitochondrial fragmentation (FUS-ALS) or elongation (SOD1-ALS). Furthermore, GA and DL restored cytoplasmic mislocalization of FUS and FUS recruitment to DNA damage sites. We further show that despite presenting an early axonal transport deficiency as well, TDP-43 patient-derived MNs did not share this mechanism. While this points towards the necessity of individualized (gene-) specific therapy stratification, it also suggests common therapeutic targets across different gene variants of ALS. Thus, we introduce a putative novel treatment for ALS based on a combination of the two substances GA and DL which might be not only an interesting novel drug candidate in subsets of ALS cases but also in other neurodegenerative diseases characterized by mitochondrial depolarization.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

DJ-1 products glycolic acid and D-lactate restore deficient axonal trafficking and DNA damage response in FUS and SOD1-associated amyotrophic lateral sclerosis

Pal,

Grossmann,

Glaß

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

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Glycolic acid and D-lactate—putative products of DJ-1—restore neurodegeneration in FUS - and SOD1-ALS

Pal,

Grossmann,

Glaß

et al. 2024

Life Sci. Alliance

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Amyotrophic lateral sclerosis (ALS) leads to death within 2–5 yr. Currently, available drugs only slightly prolong survival. We present novel insights into the pathophysiology ofSuperoxide Dismutase 1(SOD1)- and in particularFused In Sarcoma(FUS)-ALS by revealing a supposedly central role of glycolic acid (GA) and D-lactic acid (DL)—both putative products of the Parkinson’s disease associated glyoxylase DJ-1. Combined, not single, treatment with GA/DL restored axonal organelle phenotypes of mitochondria and lysosomes in FUS- and SOD1-ALS patient-derived motoneurons (MNs). This was not only accompanied by restoration of mitochondrial membrane potential but even dependent on it. Despite presenting an axonal transport deficiency as well, TDP43 patient-derived MNs did not share mitochondrial depolarization and did not respond to GA/DL treatment. GA and DL also restored cytoplasmic mislocalization of FUS and FUS recruitment to DNA damage sites, recently reported being upstream of the mitochondrial phenotypes in FUS-ALS. Whereas these data point towards the necessity of individualized (gene-) specific therapy stratification, it also suggests common therapeutic targets across different neurodegenerative diseases characterized by mitochondrial depolarization.

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FUS Is Not Mislocalized in Spinal Motor Neurons Derived From Human Induced Pluripotent Stem Cells of Main Non-FUS ALS Subtypes

Cited by 2 publications

References 13 publications

DJ-1 products glycolic acid and D-lactate restore deficient axonal trafficking and DNA damage response in FUS and SOD1-associated amyotrophic lateral sclerosis

DJ-1 products glycolic acid and D-lactate restore deficient axonal trafficking and DNA damage response in FUS and SOD1-associated amyotrophic lateral sclerosis

Glycolic acid and D-lactate—putative products of DJ-1—restore neurodegeneration in FUS - and SOD1-ALS

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