Parkin expression reverses mitochondrial dysfunction in fused in sarcoma‐induced amyotrophic lateral sclerosis

J., S.; Choi, Hyun-Jun; Kim, H.‐J.; Choi, Eui Ju; Song, Keon-Hyoung; Im, Dai Sig; Kim, K.

doi:10.1111/imb.12608

Cited by 17 publications

(11 citation statements)

References 53 publications

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“…Proteins with functions in mitochondria were highly enriched in our LLPS-dependent FUS interactome. Besides our observation that mitochondrial proteins were already dysregulated in pre-symptomatic ALS-FUS mice, others reported that cytoplasmic FUS has deleterious effects on mitochondria leading to apoptosis (Cha et al, 2019;Deng et al, 2015;Stoica et al, 2016). Therefore, we examined the impact of LLPS on FUS-mediated toxicity via mitochondria.…”

Section: Llps Is Not Required For Fus Toxicity In the Cytoplasmsupporting

confidence: 52%

The phase separation-dependent FUS interactome reveals nuclear and cytoplasmic function of liquid-liquid phase separation

Reber

Lindsay

Devoy

et al. 2019

Preprint

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Liquid-liquid phase separation (LLPS) of proteins and RNAs has emerged as the driving force underlying the formation of membrane-less organelles. Such biomolecular condensates have various biological functions and have been linked to disease. One of the best studied proteins undergoing LLPS is Fused in Sarcoma (FUS), a predominantly nuclear RNA-binding protein. Mutations in FUS have been causally linked to Amyotrophic Lateral Sclerosis (ALS), an adult-onset motor neuron disease, and LLPS followed by aggregation of cytoplasmic FUS has been proposed to be a crucial disease mechanism. In spite of this, it is currently unclear how LLPS impacts the behaviour of FUS in cells, e.g. its interactome. In order to study the consequences of LLPS on FUS and its interaction partners, we developed a method that allows for the purification of phase separated FUS-containing droplets from cell lysates. We observe substantial alterations in the interactome of FUS, depending on its biophysical state. While non-phase separated FUS interacts mainly with its well-known interaction partners involved in pre-mRNA processing, phase-separated FUS predominantly binds to proteins involved in chromatin remodelling and DNA damage repair. Interestingly, factors with function in mitochondria are strongly enriched with phase-separated FUS, providing a potential explanation for early changes in mitochondrial gene expression observed in mouse models of ALS-FUS. In summary, we present a methodology that allows to investigate the interactome of phase-separating proteins and provide evidence that LLPS strongly shapes the FUS interactome with important implications for function and disease.Wang et al., 2018) and the wash volumes applied during the co-IP exceeded the volume applied to analyse the cell lysates in Supplementary Fig. 1b, LLPS of FUS during co-IP conditions is limited to the minimum or even completely prevented. A pulldown of FLAG-eGFP served as control IP. Successful purification of the bait from droplet purifications and co-IPs were verified by SDS-PAGE followed by silver staining or western blotting, respectively ( Supplementary Fig. 2). Proteins and RNAs purified from co-IP and droplet purification experiments were analysed by means of quantitative mass spectrometry or RNA deep sequencing, respectively. Interestingly, the wild type and P525L FUS protein and RNA interactomes (under the same experimental conditions) were mostly identical ( Supplementary Fig. 3), which is why wild type and P525L interactomes from the same experimental conditions were pooled, in order to identify the most robust FUS interactors under LLPS and non-LLPS conditions. We identified 238 proteins interacting with FUS under LLPS conditions and 360 under non-LLPS conditions. 102 proteins were present in both datasets (independent of either biophysical state), resulting in 136 proteins specific to the LLPS condition. The observation that several proteins and RNAs preferentially interacted with FUS under LLPS conditions ( Fig. 1c and Supplementary Table 1) indicates th...

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Section: Llps Is Not Required For Fus Toxicity In the Cytoplasmsupporting

confidence: 52%

The phase separation-dependent FUS interactome reveals nuclear and cytoplasmic function of liquid-liquid phase separation

Reber

Lindsay

Devoy

et al. 2019

Preprint

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“…In flies expressing both FUS and FUS P525L , PINK1 and PARKIN levels are increased, while their reduction by siRNA improves neurodegenerative phenotypes caused by FUS [49]. Nonetheless, a recent study on flies shows the reversal of locomotive defects caused by FUS through PARKIN expression [50].…”

Section: Mitophagy and Alsmentioning

confidence: 98%

Mitophagy Modulation, a New Player in the Race against ALS

Madruga

Maestro

Martı́nez

2021

IJMS

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Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease that usually results in respiratory paralysis in an interval of 2 to 4 years. ALS shows a multifactorial pathogenesis with an unknown etiology, and currently lacks an effective treatment. The vast majority of patients exhibit protein aggregation and a dysfunctional mitochondrial accumulation in their motoneurons. As a result, autophagy and mitophagy modulators may be interesting drug candidates that mitigate key pathological hallmarks of the disease. This work reviews the most relevant evidence that correlate mitophagy defects and ALS, and discusses the possibility of considering mitophagy as an interesting target in the search for an effective treatment for ALS.

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“…PARKIN dysfunction is the cause of the familial form of PD (autosomal recessive juvenile Parkinsonism) and is also a risk factor for its idiopathic form [ 100 ]. PARKIN dysfunction can also cause neuronal damage in other degenerative diseases, e.g., Alzheimer’s disease, amyotrophic lateral sclerosis, multiple sclerosis, or Huntington’s disease [ 101 , 102 , 103 ]. PARK2 mutations may reduce the ubiquitinating ability for substrates such as α-synuclein or synphilin-1, leading to their toxic accumulation in the brain [ 104 , 105 ].…”

Section: Parkin Parkinson’s Disease and Cancermentioning

confidence: 99%

The Links between Parkinson’s Disease and Cancer

et al. 2020

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Epidemiologic studies indicate a decreased incidence of most cancer types in Parkinson’s disease (PD) patients. However, some neoplasms are associated with a higher risk of occurrence in PD patients. Both pathologies share some common biological pathways. Although the etiologies of PD and cancer are multifactorial, some factors associated with PD, such as α-synuclein aggregation; mutations of PINK1, PARKIN, and DJ-1; mitochondrial dysfunction; and oxidative stress can also be involved in cancer proliferation or cancer suppression. The main protein associated with PD, i.e., α-synuclein, can be involved in some types of neoplastic formations. On the other hand, however, its downregulation has been found in the other cancers. PINK1 can act as oncogenic or a tumor suppressor. PARKIN dysfunction may lead to some cancers’ growth, and its expression may be associated with some tumors’ suppression. DJ-1 mutation is involved in PD pathogenesis, but its increased expression was found in some neoplasms, such as melanoma or breast, lung, colorectal, uterine, hepatocellular, and nasopharyngeal cancers. Both mitochondrial dysfunction and oxidative stress are involved in PD and cancer development. The aim of this review is to summarize the possible associations between PD and carcinogenesis.

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Parkin expression reverses mitochondrial dysfunction in fused in sarcoma‐induced amyotrophic lateral sclerosis

Cited by 17 publications

References 53 publications

The phase separation-dependent FUS interactome reveals nuclear and cytoplasmic function of liquid-liquid phase separation

The phase separation-dependent FUS interactome reveals nuclear and cytoplasmic function of liquid-liquid phase separation

Mitophagy Modulation, a New Player in the Race against ALS

The Links between Parkinson’s Disease and Cancer

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