Trumping neurodegeneration: Targeting common pathways regulated by autosomal recessive Parkinson's disease genes

Scott, Laura Louise; Dawson, Valina L.; Dawson, Ted M.

doi:10.1016/j.expneurol.2017.04.008

Cited by 59 publications

(53 citation statements)

References 99 publications

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“…Though the disease is known to be idiopathic, perturbations in gastrointestinal function due to the accumulation of alpha-synuclein and subsequent mucosal inflammation have been implicated as major reason for the onset of this disease. The research studies thoroughly supported the fact that there is active involvement of enteric nervous system in pathological progression of this disease towards the central nervous system [115].…”

Section: Parkinson's Diseasementioning

confidence: 61%

Metabiotics: The Functional Metabolic Signatures of Probiotics: Current State-of-Art and Future Research Priorities—Metabiotics: Probiotics Effector Molecules

Singh¹,

Vishwakarma²,

Singhal³

2018

ABB

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The intricate "orchestered molecular conversation" between the host and gut microbiome is one of the most dynamic research areas in recent years. The rhythmic chemical cross talk in the form of bioactive metabolites and signalling molecules synthesized by gut microbiome plays a significant role for the modulation of human health in diversified ways. They are recognized as low molecular weight (LMW) molecules having versatile chemical attributes. They possess magnificent capability of interacting with surrounding environment and controlling the genes for various genetic, biochemical and physiological functions for maintaining the homeostasis that is now-a-days termed as "small molecules microbes originated (SMOM) homeostasis" in the host. These metabolic signatures have close structural and functional resemblance with small molecules synthesized by host eukaryotic cells and dietary components. Therefore, they may be considered as universalized metabolites contributing to the remarkable phenomenon of epigenetic regulation, cell to cell communication and stability of genome manifesting the overall growth and development of the host and known as "metabiotics". The wide panorama of utilization of probiotics is continuously expanding and conferring the major health benefits through metabiotic components are gaining tremendous momentum therefore recognized as "hidden soldiers" of the body. Therefore firstly, we outline the need and types of metabiotic molecules and depicting their role in human health. Then, we summarize their preventive and therapeutic avenues in various diseases and finally, we propose the current technological interventions, bottlenecks and future perspectives in this field that are implied for accelerating their comprehensive understanding and utilization at industrial scale.

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Section: Parkinson's Diseasementioning

confidence: 61%

Metabiotics: The Functional Metabolic Signatures of Probiotics: Current State-of-Art and Future Research Priorities—Metabiotics: Probiotics Effector Molecules

Singh¹,

Vishwakarma²,

Singhal³

2018

ABB

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“…Mitochondria dysfunction was identified as a probable cause of neuronal death in PD 22,72 . Parkin was implicated in mitochondria maintenance, particularly in elimination of damaged mitochondria, which is triggered by the ubiquitination of PINK1-phosphorylated mitofusins by parkin 17,73 .…”

Section: Discussionmentioning

confidence: 99%

Mdm2 enhances ligase activity of parkin and facilitates mitophagy

Kook

Zhan

Thibeault

et al. 2020

Sci Rep

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Loss-of-function mutations in the E3 ubiquitin ligase parkin have been implicated in the death of dopaminergic neurons in the substantia nigra, which is the root cause of dopamine deficit in the striatum in Parkinson's disease. Parkin ubiquitinates proteins on mitochondria that lost membrane potential, promoting the elimination of damaged mitochondria. Neuroprotective activity of parkin has been linked to its critical role in the mitochondria maintenance. Here we report a novel regulatory mechanism: another E3 ubiquitin ligase Mdm2 directly binds parkin and enhances its enzymatic activity in vitro and in intact cells. Mdm2 translocates to damaged mitochondria independently of parkin, enhances parkin-dependent ubiquitination of the outer mitochondria membrane protein mitofusin1. Mdm2 facilitates and its knockdown reduces parkin-dependent mitophagy. Thus, ubiquitously expressed Mdm2 might enhance cytoprotective parkin activity. The data suggest that parkin activation by Mdm2 could be targeted to increase its neuroprotective functions, which has implications for antiparkinsonian therapy.Parkin was first identified through its association with autosomal recessive juvenile parkinsonism, a familial form of Parkinson's disease (PD) with early onset 1 . Loss-of-function mutations in parkin gene, including exon deletions and rearrangements, as well as nonsense and missense mutations, are commonly associated not only with familial, but also with apparently sporadic early onset PD 2-5 . Functionally, parkin is an E3 ubiquitin ligase 6 . Initially, the studies of parkin function in PD concentrated on the search for parkin substrates and the role of parkin loss in the dysfunction of the ubiquitin-proteasome system (UBS), which appears to play a prominent role in the PD-related neurodegeneration 7 . Further studies implicated parkin in the regulation of the mitochondrial dynamics 8-10 . PINK1, another protein associated with a recessive form of early onset familial PD 11 , acts upstream of parkin, recruiting parkin to damaged mitochondria and stimulating its ligase activity 10,12-15 . Parkin then ubiquitinates proteins of the outer mitochondrial membrane causing their proteosomal degradation and elimination of the damaged mitochondria via mitophagy [16][17][18][19] . Mitochondrial dysfunction has been implicated in PD 20-23 , although the role of mitophagy in the quality control of neuronal mitochondria remains controversial [24][25][26] . Parkin exists in an autoinhibited basal state [27][28][29][30] . Its activity is regulated, in addition to the PINK1-dependent phosphorylation 15,31,32 , via a variety of mechanisms including formation of multiprotein signaling complexes [33][34][35] . Full spectrum of parkin interactions that regulate its activity is not yet understood. However, it is clear that this regulation is complex and often involves scaffolding proteins 36 , which may impact on parkin-dependent control of the mitochondrial dynamics and, consequently, its functions in the normal and diseased brain.We have recently de...

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“…It is believed that PRKN variants impair mitochondrial homeostasis, ultimately leading to neuronal cell death (Scott, Dawson, & Dawson, 2017). Biallelic mutations in PRKN are required for a clinical phenotype (Abbas et al., 1999; Kitada et al., 1998).…”

Section: Introductionmentioning

confidence: 99%

Phase determination using chromosomal microarray and fluorescence in situ hybridization in a patient with early onset Parkinson disease and two deletions in PRKN

Williams

Barrett

Dhamija

et al. 2018

Molec Gen & Gen Med

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BackgroundMutations in the parkin gene (PRKN) are the most commonly identified genetic factors in early onset Parkinson disease (EOPD), with biallelic mutations, resulting in a clinical phenotype. However, normal variation is also common in PRKN, particularly in the form of copy number variation (CNV), challenging interpretation of genetic testing results. Here we report a case of a 29‐year‐old male with EOPD and two deletions in PRKN detected by chromosomal microarray (CMA).MethodsThe proband was clinically examined by a neurologist for postural instability with frequent falls, bradykinesia, gait freezing with festination, and hypophonia. Chromosomal microarray analysis (CMA) was performed on the proband and his parents using the Affymetrix CytoScan HD microarray. Subsequent fluorescence in situ hybridization (FISH) was performed on the proband and both parents.ResultsChromosomal microarray detected the presence of two deletions of PRKN in the proband. Parental CMA analysis was performed to determine the clinical significance of this finding, as well as to demonstrate phase of these deletions. Parental CMA revealed that one deletion was paternally inherited and one deletion was de novo. A custom FISH approach was then successfully used to phase the deletions.ConclusionChromosomal microarray and fluorescence in situ hybridization analysis of this trio identified two deletions in PRKN occurring in trans, providing a genetic etiology for the clinical diagnosis of EOPD. The determination of inheritance and phase of the deletions was critical to the proper interpretation of these results. These findings highlight the utility of CMA in the detection of clinically relevant CNVs in cases of EOPD, and also serve to emphasize the importance of follow‐up FISH and parental testing.

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Trumping neurodegeneration: Targeting common pathways regulated by autosomal recessive Parkinson's disease genes

Cited by 59 publications

References 99 publications

Metabiotics: The Functional Metabolic Signatures of Probiotics: Current State-of-Art and Future Research Priorities—Metabiotics: Probiotics Effector Molecules

Metabiotics: The Functional Metabolic Signatures of Probiotics: Current State-of-Art and Future Research Priorities—Metabiotics: Probiotics Effector Molecules

Mdm2 enhances ligase activity of parkin and facilitates mitophagy

Phase determination using chromosomal microarray and fluorescence in situ hybridization in a patient with early onset Parkinson disease and two deletions in PRKN

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