Parkin is a disease modifier in the mutant
            <scp>SOD</scp>
            1 mouse model of
            <scp>ALS</scp>

Palomo, Gloria M.; Granatiero, Veronica; Kawamata, Hibiki; Konràd, Csaba; Kim, Michelle; Arreguin, Andrea J.; Zhao, Dazhi; Milner, Teresa A.; Manfredi, Giovanni

doi:10.15252/emmm.201808888

Cited by 65 publications

(52 citation statements)

References 88 publications

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“…Knocking down Parkin can reverse such negative effect and improve the pathological symptoms of ALS. But the effect is not sustained and may be compensated by other ubiquitinating enzymes …”

Section: Mitophagy and Neurodegenerative Diseasesmentioning

confidence: 99%

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Mechanisms and roles of mitophagy in neurodegenerative diseases

2019

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Mitochondria are double‐membrane‐encircled organelles existing in most eukaryotic cells and playing important roles in energy production, metabolism, Ca 2+ buffering, and cell signaling. Mitophagy is the selective degradation of mitochondria by autophagy. Mitophagy can effectively remove damaged or stressed mitochondria, which is essential for cellular health. Thanks to the implementation of genetics, cell biology, and proteomics approaches, we are beginning to understand the mechanisms of mitophagy, including the roles of ubiquitin‐dependent and receptor‐dependent signals on damaged mitochondria in triggering mitophagy. Mitochondrial dysfunction and defective mitophagy have been broadly associated with neurodegenerative diseases. This review is aimed at summarizing the mechanisms of mitophagy in higher organisms and the roles of mitophagy in the pathogenesis of neurodegenerative diseases. Although many studies have been devoted to elucidating the mitophagy process, a deeper understanding of the mechanisms leading to mitophagy defects in neurodegenerative diseases is required for the development of new therapeutic interventions, taking into account the multifactorial nature of diseases and the phenotypic heterogeneity of patients.

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“…Knocking down Parkin can reverse such negative effect and improve the pathological symptoms of ALS. But the effect is not sustained and may be compensated by other ubiquitinating enzymes …”

Section: Mitophagy and Neurodegenerative Diseasesmentioning

confidence: 99%

“…177 As found in recent studies, OPTN will translocate to damaged mitochondria, which is dependent on Parkin ubiquitination of mitochondria. 175 169,183,184 In addition, VCP also exhibits some properties similar to OPTN;…”

Section: Optn/tbk1mentioning

confidence: 99%

Mechanisms and roles of mitophagy in neurodegenerative diseases

2019

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“…Nevertheless, CHCHD10 S59L expression induced PINK1 stabilization in mitochondria without strong disruption of mitochondrial membrane potential, and genetic/pharmacologic inhibition of PINK1 mitigated CHCHD10 S59L -induced toxicity. Reducing PINK1 or parkin-mediated pathways are beneficial in in vivo disease models of SOD1, FUS, and TARDBP mutations (55)(56)(57). We demonstrated that MFN2 agonists enhanced ATP production in flies expressing C9ORF72 with GGGGCC repeats.…”

Section: Discussionmentioning

confidence: 79%

Dominant toxicity of ALS–FTD-associated CHCHD10^S59L is mediated by TDP-43 and PINK1

Baek

Choe

Dorn³

et al. 2019

Preprint

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†Authors contributed equally.One Sentence Summary: Inhibition of TDP-43 mitochondrial translocation or PINK1 kinase activity mitigates CHCHD10 S59L -mediated mitochondrial toxicity. AbstractMutations in coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10) are a genetic cause of amyotrophic lateral sclerosis and/or frontotemporal dementia (ALS-FTD). To elucidate how mutations in CHCHD10 induce disease, we generated a Drosophila melanogaster model of CHCHD10-mediated ALS-FTD. Expression of CHCHD10 S59L in Drosophila caused gain-offunction toxicity in eyes, motor neurons, and muscles, in addition to mitochondrial defects in flies and HeLa cells. TDP-43 and PINK1 formed two axes, driving the mutant-dependent phenotypes. CHCHD10 S59L expression increased TDP-43 insolubility and mitochondrial translocation. Blocking mitochondrial translocation with a peptide inhibitor reduced CHCHD10 S59L -mediated toxicity. PINK1 knockdown rescued CHCHD10 S59L -mediated phenotypes in Drosophila and HeLa cells. The two PINK1 substrates mitofusin and mitofilin were genetic modifiers of this phenotype. Mitofusin agonists reversed the CHCHD10 S59Linduced phenotypes in Drosophila and HeLa cells and increased ATP production in Drosophila expressing C9orf72 with expanded GGGGCC repeats. Two peptides inhibitors of PINK1 mitigated the mitochondrial defects introduced by CHCHD10 S59L expression. These findings indicate that TDP-43 mitochondrial translocation and chronic activation of PINK1-mediated pathways by CHCHD10 S59L generate dominant toxicity. Therefore, inhibiting PINK1 activity may provide a therapeutic strategy for CHCHD10-associated disease.

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“…In our VCP fly model, the defects of mitochondrial transport are not identical to those in the SOD1 model, yet upregulation of Miro is beneficial in both models (Figure 3). Similarly in a SOD1 mouse model of ALS, reducing Parkin has been found to delay the loss of Miro, slow motor neuron loss, and prolong survival (Palomo et al, 2018). These findings indicate that Miro may be a converging therapeutic target in genetically distinct ALS/FTD patients.…”

Section: Discussionmentioning

confidence: 80%

Drosophila VCP/p97 Mediates Dynein-Dependent Retrograde Mitochondrial Motility in Axons

Gonzalez

Wang

2020

Front. Cell Dev. Biol.

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Valosin-containing protein (VCP), also called p97, is an evolutionarily conserved and ubiquitously expressed ATPase with diverse cellular functions. Dominant mutations in VCP are found in a late-onset multisystem degenerative proteinopathy. The neurological manifestations of the disorder include frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). In these patients, long motor neuron axons could be particularly susceptible to defects in axonal transport. However, whether VCP has a physiological function in maintaining axonal transport and whether this role is impaired by disease-causing mutations remains elusive. Here, by employing live-imaging methods in Drosophila larval axons and performing genetic interaction experiments, we discover that VCP regulates the axonal transport of mitochondria. Downregulation of VCP enhances the retrograde transport of mitochondria and reduces the density of mitochondria in larval axons. This unidirectional motility phenotype is rescued by removing one copy of the retrograde motor dynein heavy chain (DHC), or elevating Miro which facilitates anterograde mitochondrial movement by interacting with the anterograde motor kinesin heavy chain (KHC). Importantly, Miro upregulation also significantly improves ATP production of VCP mutant larvae. We investigate human VCP pathogenic mutations in our fly system. We find that expressing these mutations affects mitochondrial transport in the same way as knocking down VCP. Our results reveal a new role of VCP in mediating axonal mitochondrial transport, and provide evidence implicating impaired mitochondrial motility in the pathophysiology of VCP-relevant neurodegenerative diseases.

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Parkin is a disease modifier in the mutant SOD 1 mouse model of ALS

Cited by 65 publications

References 88 publications

Mechanisms and roles of mitophagy in neurodegenerative diseases

Mechanisms and roles of mitophagy in neurodegenerative diseases

Dominant toxicity of ALS–FTD-associated CHCHD10^S59L is mediated by TDP-43 and PINK1

Drosophila VCP/p97 Mediates Dynein-Dependent Retrograde Mitochondrial Motility in Axons

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Parkin is a disease modifier in the mutant SOD 1 mouse model of ALS

Cited by 65 publications

References 88 publications

Mechanisms and roles of mitophagy in neurodegenerative diseases

Mechanisms and roles of mitophagy in neurodegenerative diseases

Dominant toxicity of ALS–FTD-associated CHCHD10S59L is mediated by TDP-43 and PINK1

Drosophila VCP/p97 Mediates Dynein-Dependent Retrograde Mitochondrial Motility in Axons

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Dominant toxicity of ALS–FTD-associated CHCHD10^S59L is mediated by TDP-43 and PINK1