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Article ; Online: Blocking the Self-Destruct Program of Dopamine Neurons through Macrophage Migration Inhibitory Factor Nuclease Inhibition.

Patel, Jaimin / Dawson, Valina L / Dawson, Ted M

Movement disorders : official journal of the Movement Disorder Society

2024 Volume 39, Issue 4, Page(s) 644–650

Abstract: Parkinson's disease (PD) is a progressive neurodegenerative condition that pathognomonically involves the death of dopaminergic neurons in the substantia nigra pars compacta, resulting in a myriad of motor and non-motor symptoms. Given the insurmountable ...

Abstract	Parkinson's disease (PD) is a progressive neurodegenerative condition that pathognomonically involves the death of dopaminergic neurons in the substantia nigra pars compacta, resulting in a myriad of motor and non-motor symptoms. Given the insurmountable burden of this disease on the population and healthcare system, significant efforts have been put forth toward generating disease modifying therapies. This class of treatments characteristically alters disease course, as opposed to current strategies that focus on managing symptoms. Previous literature has implicated the cell death pathway known as parthanatos in PD progression. Inhibition of this pathway by targeting poly (ADP)-ribose polymerase 1 (PARP1) prevents neurodegeneration in a model of idiopathic PD. However, PARP1 has a vast repertoire of functions within the body, increasing the probability of side effects with the long-term treatment likely necessary for clinically significant neuroprotection. Recent work culminated in the development of a novel agent targeting the macrophage migration inhibitory factor (MIF) nuclease domain, also named parthanatos-associated apoptosis-inducing factor nuclease (PAAN). This nuclease activity specifically executes the terminal step in parthanatos. Parthanatos-associated apoptosis-inducing factor nuclease inhibitor-1 was neuroprotective in multiple preclinical mouse models of PD. This piece will focus on contextualizing this discovery, emphasizing its significance, and discussing its potential implications for parthanatos-directed treatment. © 2024 International Parkinson and Movement Disorder Society.
MeSH term(s)	Humans ; Dopaminergic Neurons/metabolism ; Parkinson Disease/metabolism ; Animals ; Macrophage Migration-Inhibitory Factors/metabolism ; Macrophage Migration-Inhibitory Factors/antagonists & inhibitors ; Poly (ADP-Ribose) Polymerase-1/metabolism ; Parthanatos/drug effects
Chemical Substances	Macrophage Migration-Inhibitory Factors ; Poly (ADP-Ribose) Polymerase-1 (EC 2.4.2.30)
Language	English
Publishing date	2024-02-23
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	607633-6
ISSN	1531-8257 ; 0885-3185
ISSN (online)	1531-8257
ISSN	0885-3185
DOI	10.1002/mds.29748
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Book: Parkinson's disease

Dawson, Ted M.

genetics and pathogenesis

(Neurological disease and therapy ; 83)

2007

Author's details	ed. by Ted M. Dawson
Series title	Neurological disease and therapy ; 83
Collection
Keywords	Parkinson Disease / genetics ; Parkinson Disease / physiopathology
Language	English
Size	IX, 386 S. : Ill., graph. Darst.
Publisher	Informa Healthcare
Publishing place	New York u.a.
Publishing country	United States
Document type	Book
HBZ-ID	HT014815212
ISBN	0-8493-3697-X ; 978-0-8493-3697-3
Database	Catalogue ZB MED Medicine, Health

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Shelf mark	Loan status	Location
2007 A 3145	order for loan	Magazin

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Article ; Online: Protein Translation in the Pathogenesis of Parkinson's Disease.

Ashraf, Daniyal / Khan, Mohammed Repon / Dawson, Ted M / Dawson, Valina L

International journal of molecular sciences

2024 Volume 25, Issue 4

Abstract: In recent years, research into Parkinson's disease and similar neurodegenerative disorders has increasingly suggested that these conditions are synonymous with failures in proteostasis. However, the spotlight of this research has remained firmly focused ... ...

Abstract	In recent years, research into Parkinson's disease and similar neurodegenerative disorders has increasingly suggested that these conditions are synonymous with failures in proteostasis. However, the spotlight of this research has remained firmly focused on the tail end of proteostasis, primarily aggregation, misfolding, and degradation, with protein translation being comparatively overlooked. Now, there is an increasing body of evidence supporting a potential role for translation in the pathogenesis of PD, and its dysregulation is already established in other similar neurodegenerative conditions. In this paper, we consider how altered protein translation fits into the broader picture of PD pathogenesis, working hand in hand to compound the stress placed on neurons, until this becomes irrecoverable. We will also consider molecular players of interest, recent evidence that suggests that aggregates may directly influence translation in PD progression, and the implications for the role of protein translation in our development of clinically useful diagnostics and therapeutics.
MeSH term(s)	Humans ; Parkinson Disease/etiology ; Parkinson Disease/metabolism ; Neurons/metabolism ; Proteostasis ; Protein Biosynthesis ; alpha-Synuclein/metabolism
Chemical Substances	alpha-Synuclein
Language	English
Publishing date	2024-02-18
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms25042393
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Article ; Online: Parthanatos: Mechanisms, modulation, and therapeutic prospects in neurodegenerative disease and stroke.

Yang, Liu / Guttman, Lauren / Dawson, Valina L / Dawson, Ted M

Biochemical pharmacology

2024 , Page(s) 116174

Abstract: Parthanatos is a cell death signaling pathway that has emerged as a compelling target for pharmaceutical intervention. It plays a pivotal role in the neuron loss and neuroinflammation that occurs in Parkinson's Disease (PD), Alzheimer's Disease (AD), ... ...

Abstract	Parthanatos is a cell death signaling pathway that has emerged as a compelling target for pharmaceutical intervention. It plays a pivotal role in the neuron loss and neuroinflammation that occurs in Parkinson's Disease (PD), Alzheimer's Disease (AD), Huntington's Disease (HD), Amyotrophic Lateral Sclerosis (ALS), and stroke. There are currently no treatments available to humans to prevent cell death in any of these diseases. This review provides an in-depth examination of the current understanding of the Parthanatos mechanism, with a particular focus on its implications in neuroinflammation and various diseases discussed herein. Furthermore, we thoroughly review potential intervention targets within the Parthanatos pathway. We dissect recent progress in inhibitory strategies, complimented by a detailed structural analysis of key Parthanatos executioners, PARP-1, AIF, and MIF, along with an assessment of their established inhibitors. We hope to introduce a new perspective on the feasibility of targeting components within the Parthanatos pathway, emphasizing its potential to bring about transformative outcomes in therapeutic interventions. By delineating therapeutic opportunities and known targets, we seek to emphasize the imperative of blocking Parthanatos as a precursor to developing disease-modifying treatments. This comprehensive exploration aims to catalyze a paradigm shift in our understanding of potential neurodegenerative disease therapeutics, advocating for the pursuit of effective interventions centered around Parthanatos inhibition.
Language	English
Publishing date	2024-03-27
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	208787-x
ISSN	1873-2968 ; 0006-2952
ISSN (online)	1873-2968
ISSN	0006-2952
DOI	10.1016/j.bcp.2024.116174
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Article ; Online: Pharmacologic inhibition of MIF nuclease: A new treatment paradigm to treat cell death.

Biswas, Devanik / Dawson, Valina L / Dawson, Ted M

Clinical and translational medicine

2022 Volume 12, Issue 9, Page(s) e1044

MeSH term(s)	Cell Death ; Endonucleases ; Macrophage Migration-Inhibitory Factors/genetics ; Macrophage Migration-Inhibitory Factors/metabolism
Chemical Substances	Macrophage Migration-Inhibitory Factors ; Endonucleases (EC 3.1.-)
Language	English
Publishing date	2022-10-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2697013-2
ISSN	2001-1326 ; 2001-1326
ISSN (online)	2001-1326
ISSN	2001-1326
DOI	10.1002/ctm2.1044
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Article ; Online: DNA Methylation Signature of Aging: Potential Impact on the Pathogenesis of Parkinson's Disease.

Yazar, Volkan / Dawson, Valina L / Dawson, Ted M / Kang, Sung-Ung

Journal of Parkinson's disease

2023 Volume 13, Issue 2, Page(s) 145–164

Abstract: Regulation of gene expression by epigenetic modifications means lasting and heritable changes in the function of genes without alterations in the DNA sequence. Of all epigenetic mechanisms identified thus far, DNA methylation has been of particular ... ...

Abstract	Regulation of gene expression by epigenetic modifications means lasting and heritable changes in the function of genes without alterations in the DNA sequence. Of all epigenetic mechanisms identified thus far, DNA methylation has been of particular interest in both aging and age-related disease research over the last decade given the consistency of site-specific DNA methylation changes during aging that can predict future health and lifespan. An increasing line of evidence has implied the dynamic nature of DNA (de)methylation events that occur throughout the lifespan has a role in the pathophysiology of aging and age-associated neurodegenerative conditions, including Parkinson's disease (PD). In this regard, PD methylome shows, to some extent, similar genome-wide changes observed in the methylome of healthy individuals of matching age. In this review, we start by providing a brief overview of studies outlining global patterns of DNA methylation, then its mechanisms and regulation, within the context of aging and PD. Considering diverging lines of evidence from different experimental and animal models of neurodegeneration and how they combine to shape our current understanding of tissue-specific changes in DNA methylome in health and disease, we report a high-level comparison of the genomic methylation landscapes of brain, with an emphasis on dopaminergic neurons in PD and in natural aging. We believe this will be particularly useful for systematically dissecting overlapping genome-wide alterations in DNA methylation during PD and healthy aging, and for improving our knowledge of PD-specific changes in methylation patterns independent of aging process.
MeSH term(s)	Animals ; DNA Methylation ; Parkinson Disease/metabolism ; Epigenesis, Genetic ; Aging/genetics ; Aging/metabolism ; Epigenome
Language	English
Publishing date	2023-01-30
Publishing country	Netherlands
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2620609-2
ISSN	1877-718X ; 1877-7171
ISSN (online)	1877-718X
ISSN	1877-7171
DOI	10.3233/JPD-223517
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Article ; Online: Promising disease-modifying therapies for Parkinson's disease.

Dawson, Valina L / Dawson, Ted M

Science translational medicine

2020 Volume 11, Issue 520

Abstract: To date, there is no disease-modifying therapy for Parkinson's disease; however, promising new agents have advanced into clinical trials. ...

Abstract	To date, there is no disease-modifying therapy for Parkinson's disease; however, promising new agents have advanced into clinical trials.
MeSH term(s)	Clinical Trials as Topic ; Genetic Predisposition to Disease ; Humans ; Parkinson Disease/genetics ; Parkinson Disease/pathology ; Parkinson Disease/therapy
Language	English
Publishing date	2020-04-27
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2518854-9
ISSN	1946-6242 ; 1946-6234
ISSN (online)	1946-6242
ISSN	1946-6234
DOI	10.1126/scitranslmed.aba1659
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Article ; Online: Cell Biology of Parkin: Clues to the Development of New Therapeutics for Parkinson's Disease.

Patel, Jaimin / Panicker, Nikhil / Dawson, Valina L / Dawson, Ted M

CNS drugs

2022 Volume 36, Issue 12, Page(s) 1249–1267

Abstract: Parkinson's disease is the second most prevalent neurodegenerative disease and contributes significantly to morbidity globally. Currently, no disease-modifying therapies exist to combat this disorder. Insights from the molecular and cellular pathobiology ...

Abstract	Parkinson's disease is the second most prevalent neurodegenerative disease and contributes significantly to morbidity globally. Currently, no disease-modifying therapies exist to combat this disorder. Insights from the molecular and cellular pathobiology of the disease seems to indicate promising therapeutic targets. The parkin protein has been extensively studied for its role in autosomal recessive Parkinson's disease and, more recently, its role in sporadic Parkinson's disease. Parkin is an E3 ubiquitin ligase that plays a prominent role in mitochondrial quality control, mitochondrial-dependent cell death pathways, and other diverse functions. Understanding the numerous roles of parkin has introduced many new possibilities for therapeutic modalities in treating both autosomal recessive Parkinson's disease and sporadic Parkinson's disease. In this article, we review parkin biology with an emphasis on mitochondrial-related functions and propose novel, potentially disease-modifying therapeutic approaches for treating this debilitating condition.
MeSH term(s)	Humans ; Parkinson Disease/drug therapy ; Parkinson Disease/metabolism ; Neurodegenerative Diseases/metabolism ; Ubiquitin-Protein Ligases/genetics ; Ubiquitin-Protein Ligases/metabolism ; Mitochondria/metabolism
Chemical Substances	parkin protein (EC 2.3.2.27) ; Ubiquitin-Protein Ligases (EC 2.3.2.27)
Language	English
Publishing date	2022-11-15
Publishing country	New Zealand
Document type	Review ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1203800-3
ISSN	1179-1934 ; 1172-7047
ISSN (online)	1179-1934
ISSN	1172-7047
DOI	10.1007/s40263-022-00973-7
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Zs.A 4083: Show issues

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Article: Targeting Parthanatos in Ischemic Stroke.

Koehler, Raymond C / Dawson, Valina L / Dawson, Ted M

Frontiers in neurology

2021 Volume 12, Page(s) 662034

Abstract: Parthanatos is a cell death signaling pathway in which excessive oxidative damage to DNA leads to over-activation of poly(ADP-ribose) polymerase (PARP). PARP then generates the formation of large poly(ADP-ribose) polymers that induce the release of ... ...

Abstract	Parthanatos is a cell death signaling pathway in which excessive oxidative damage to DNA leads to over-activation of poly(ADP-ribose) polymerase (PARP). PARP then generates the formation of large poly(ADP-ribose) polymers that induce the release of apoptosis-inducing factor from the outer mitochondrial membrane. In the cytosol, apoptosis-inducing factor forms a complex with macrophage migration inhibitory factor that translocates into the nucleus where it degrades DNA and produces cell death. In a review of the literature, we identified 24 publications from 13 laboratories that support a role for parthanatos in young male mice and rats subjected to transient and permanent middle cerebral artery occlusion (MCAO). Investigators base their conclusions on the use of nine different PARP inhibitors (19 studies) or PARP1-null mice (7 studies). Several studies indicate a therapeutic window of 4-6 h after MCAO. In young female rats, two studies using two different PARP inhibitors from two labs support a role for parthanatos, whereas two studies from one lab do not support a role in young female PARP1-null mice. In addition to parthanatos, a body of literature indicates that PARP inhibitors can reduce neuroinflammation by interfering with NF-κB transcription, suppressing matrix metaloproteinase-9 release, and limiting blood-brain barrier damage and hemorrhagic transformation. Overall, most of the literature strongly supports the scientific premise that a PARP inhibitor is neuroprotective, even when most did not report behavior outcomes or address the issue of randomization and treatment concealment. Several third-generation PARP inhibitors entered clinical oncology trials without major adverse effects and could be repurposed for stroke. Evaluation in aged animals or animals with comorbidities will be important before moving into clinical stroke trials.
Language	English
Publishing date	2021-05-05
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2564214-5
ISSN	1664-2295
ISSN	1664-2295
DOI	10.3389/fneur.2021.662034
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Article ; Online: Integration of Human Induced Pluripotent Stem Cell (hiPSC)-Derived Neurons into Rat Brain Circuits.

Yin, Xiling / Dawson, Ted M / Dawson, Valina L

Bio-protocol

2020 Volume 10, Issue 17, Page(s) e3746

Abstract: Human neuron transplantation offers novel opportunities for modeling human neurologic diseases and potentially replacement therapies. However, the complex structure of the human cerebral cortex, which is organized in six layers with tightly ... ...

Abstract	Human neuron transplantation offers novel opportunities for modeling human neurologic diseases and potentially replacement therapies. However, the complex structure of the human cerebral cortex, which is organized in six layers with tightly interconnected excitatory and inhibitory neuronal networks, presents significant challenges for
Language	English
Publishing date	2020-09-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	2833269-6
ISSN	2331-8325 ; 2331-8325
ISSN (online)	2331-8325
ISSN	2331-8325
DOI	10.21769/BioProtoc.3746
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