Parkin-mediated reduction of nuclear and soluble TDP-43 reverses behavioral decline in symptomatic mice

Chen, Wenqiang; Lonskaya, Irina; Hebron, Michaeline; Ibrahim, Zainab; Olszewski, Rafal T.; Neale, Joseph H.; Moussa, Charbel

doi:10.1093/hmg/ddu211

Cited by 35 publications

(46 citation statements)

References 33 publications

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“…Studies of ALS/FTLD patients, as well as cell culture experiments, have shown that TDP-43 colocalizes with TIA-1, suggesting that TDP-43 aggregates are actually SGs (Liu-Yesucevitz, et al, 2010). However, we found that re-localization of TDP-43 in the cytoplasm is protective (Chen, et al, 2014; Hebron, et al, 2013), suggesting that TDP-43 aggregation in the cytosol may prevent aberrant TDP-43 binding and reduce its pathologic effects. In addition, reduction of soluble and nuclear TDP-43 leads to neuronal protection, independent of protein solubility (Chen, et al, 2014).…”

Section: Tdp-43 Protein Aggregationmentioning

confidence: 82%

“…However, we found that re-localization of TDP-43 in the cytoplasm is protective (Chen, et al, 2014; Hebron, et al, 2013), suggesting that TDP-43 aggregation in the cytosol may prevent aberrant TDP-43 binding and reduce its pathologic effects. In addition, reduction of soluble and nuclear TDP-43 leads to neuronal protection, independent of protein solubility (Chen, et al, 2014). …”

Section: Tdp-43 Protein Aggregationmentioning

confidence: 82%

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TDP-43 in the spectrum of MND-FTLD pathologies

Heyburn

Moussa

2017

Molecular and Cellular Neuroscience

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The relationship between RNA-binding proteins, particularly TAR DNA binding protein 43 (TDP-43), and neurodegeneration is an important area of research. TDP-43 is involved in so many cellular processes that perturbation of protein homeostasis can lead to countless downstream effects. Understanding what leads to this disease-related protein imbalance and the resulting cellular and molecular effects will help to develop targets for disease intervention, whether it be prevention of protein accumulation, or addressing a secondary effect of protein accumulation. Here we review the current literature of TDP-43 and TDP-43 pathologies, the effects of TDP-43 overexpression and disruption of synaptic proteins through its binding of messenger RNA, leading to synaptic dysfunction. This review highlights some of the still-limited knowledge of the protein TDP-43 and how it can contribute to disease.

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Section: Tdp-43 Protein Aggregationmentioning

confidence: 82%

Section: Tdp-43 Protein Aggregationmentioning

confidence: 82%

TDP-43 in the spectrum of MND-FTLD pathologies

Heyburn

Moussa

2017

Molecular and Cellular Neuroscience

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“…For instance: sunitinib was reported to reduce hypoxia-induced cerebral dysfunction and edema formation in rat brains (Saraswat, Nehra, Chaudhary, & Prasad, 2015). Nilotinib was reported to reduce neurodegeneration in a TDP-43 induced model of ALS (Wenqiang et al, 2014), AD model (Lonskaya, Hebron, Selby, Turner, & Moussa, 2015), as well as MPTP-induced and α-synuclein overexpression PD models (Hebron, Lonskaya, & Moussa, 2013; Karuppagounder et al, 2014). Dasatinib was shown to improve memory and decrease microglia activation in AD mice (Dhawan & Combs, 2012), to delay the onset of EAE (Azizi, Goudarzvand, Afraei, Sedaghat, & Mirshafiey, 2015), and to extend survival and motor skills in SOD1 G93A ALS mice (Katsumata et al, 2012).…”

Section: Tpa – Pdgf-cc – Pdgfr-α Signaling Axis In the Cns: Means mentioning

confidence: 99%

Pharmacological targeting of the PDGF-CC signaling pathway for blood–brain barrier restoration in neurological disorders

Lewandowski

Fredriksson

Lawrence

et al. 2016

Pharmacology & Therapeutics

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Neurological disorders account for a majority of non-malignant disability in humans and are often associated with dysfunction of the blood-brain barrier (BBB). Recent evidence shows that despite apparent variation in the origin of neural damage, the central nervous system has a common injury response mechanism involving platelet-derived growth factor (PDGF)-CC activation in the neurovascular unit and subsequent dysfunction of BBB integrity. Inhibition of PDGF-CC signaling with imatinib in mice has been shown to prevent BBB dysfunction and have neuroprotective effects in acute damage conditions, including traumatic brain injury, seizures or stroke, as well as in neurodegenerative diseases that develop over time, including multiple sclerosis and amyotrophic lateral sclerosis. Stroke and traumatic injuries are major risk factors for age-associated neurodegenerative disorders and we speculate that restoring BBB properties through PDGF-CC inhibition might provide a common therapeutic opportunity for treatment of both acute and progressive neuropathology in humans. In this review we will summarize what is known about the role of PDGF-CC in neurovascular signaling events and the variety of seemingly different neuropathologies it is involved in. We will also discuss the pharmacological means of therapeutic interventions for anti-PDGF-CC therapy and ongoing clinical trials. In summary: inhibition of PDGF-CC signaling can be protective for immediate injury and decrease the long-term neurodegenerative consequences.

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“…TDP-43 is a predominantly nuclear protein, but abnormal cytosolic and/or nuclear aggregation of this protein are linked to many diseases, including ALS and FTLD [115,116,117,118,119,120,121]. Parkin ubiquitinates TDP-43 and facilitates TDP-43 aggresome formation in the cytosol [114,122,123]. We recently demonstrated that tyrosine kinase-induced Parkin activity results in the translocation of nuclear TDP-43 into the cytosol and degradation via autophagy [122].…”

Section: Parkin and The Aggresomementioning

confidence: 99%

“…Parkin ubiquitinates TDP-43 and facilitates TDP-43 aggresome formation in the cytosol [114,122,123]. We recently demonstrated that tyrosine kinase-induced Parkin activity results in the translocation of nuclear TDP-43 into the cytosol and degradation via autophagy [122]. TDP-43 overexpression reduces TCA metabolism and alters amino acid levels, causing neuronal death in vivo [124].…”

Section: Parkin and The Aggresomementioning

confidence: 99%

Parkin Is Dispensable for Mitochondrial Function, but Its Ubiquitin Ligase Activity Is Critical for Macroautophagy and Neurotransmitters: Therapeutic Potential beyond Parkinson's Disease

Moussa

2015

Neurodegener Dis

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Parkin biology has emerged as an exciting area of pharmaceutical development for several human diseases, including cancer and neurodegeneration. Parkin's role is multifaceted in human health and disease and its function affecting major cellular quality control mechanisms, including the ubiquitin-proteasome and autophagy-lysosome systems, is critical in the maintenance of cellular homeostasis. Loss of Parkin function due to aging, protein instability and gene mutations is manifest in a number of human diseases, contributing to the validation of this protein as a therapeutic target. Parkin activation to mobilize cellular quality control mechanisms and counteract dyshomeostasis is a highly desirable area for therapeutic development. The elucidation of Parkin's crystal structure and better understanding of possible posttranslational modifications (i.e. phosphorylation, ubiquitination, etc.) that regulate Parkin's enzymatic activity suggest that this protein is a therapeutic drug target in many human diseases. Here we review Parkin's role in health and disease and discuss the effects of self-ubiquitination and deubiquitination on Parkin activity. This review provides further evidence showing the longitudinal effects of Parkin deletion on mitochondrial function, oxidative stress and neurotransmitter balance in vivo using high-frequency ¹H/¹³C NMR spectroscopy.

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Parkin-mediated reduction of nuclear and soluble TDP-43 reverses behavioral decline in symptomatic mice

Cited by 35 publications

References 33 publications

TDP-43 in the spectrum of MND-FTLD pathologies

TDP-43 in the spectrum of MND-FTLD pathologies

Pharmacological targeting of the PDGF-CC signaling pathway for blood–brain barrier restoration in neurological disorders

Parkin Is Dispensable for Mitochondrial Function, but Its Ubiquitin Ligase Activity Is Critical for Macroautophagy and Neurotransmitters: Therapeutic Potential beyond Parkinson's Disease

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