Targeted Downregulation of Estradiol Binding Na+/H+ Exchanger Nhx-2, Mimics Calorie Restriction, Extends Reproductive Longevity and Ameliorates Effects Associated With Alpha Synuclein Aggregation In C. Elegans

2021 ◽  
Author(s):  
Shikha Shukla ◽  
Lalit Kumar ◽  
Arunabh Sarkar ◽  
Kottapalli Srivi ◽  
Aamir Nazir
Keyword(s):  
Reproductive Health ◽  
Neurodegenerative Diseases ◽  
Functional Characterization ◽  
Alpha Synuclein ◽  
Binding Potential ◽  
Estradiol Treatment ◽  
Reproductive Senescence ◽  
Knock Out ◽  
C Elegans ◽  
Alpha Synuclein Aggregation

Abstract Setting in of reproductive senescence (RS) gives rise to several changes, making aged individuals susceptible to multiple disorders including neurodegenerative diseases, cardiovascular ailments and bone disorders amongst others. The present study, employing transgenic C. elegans that expresses ‘human’ alpha synuclein, endeavors to decipher the association of reproductive senescence with age-associated neurodegenerative diseases and behavioral ageing, under normal conditions and after being probed with estradiol. We carried out RNAi induced silencing of a subset of 22 genes that are known to delay RS, followed by studies on alpha-Synuclein aggregation and associated effects. These studies led us to functional characterization of the Na+/H+ exchanger; nhx-2, expressed exclusively in gut. We found that RNAi of nhx-2 not only ameliorates the effects associated with alpha-Synuclein aggregation, but it also attunes effects related to behavioral aging including that of reproductive health-span and neuroprotection via mimicking dietary restriction, as it alters food absorption from the gut. We further elucidated that these effects are Sir-2.1 driven as nhx-2 knock out did not delay reproductive senescence in knock down condition of sir-2.1. To substantiate our findings, we performed whole transcriptome analysis in nhx-2 mutant strain. Our data revealed differential expression of 61 out of 62 hallmark genes of CR described by GenDR, in knock out condition of nhx-2. As estradiol plays a central role in both reproductive health as well as neuronal health, we subjected worms to exogenous estradiol treatment and observed that it led to elevated levels of nhx-2. Studies on structural binding analysis demonstrated significant binding potential of estradiol receptor NHR-14 with nhx-2 gene and ChIP analysis revealed that estradiol treatment gives rise to enhanced NHX-2 levels through inducing the promoter specific histone H3 acetylation (H3K9) and lysine methylation (H3K4me3). These studies identify nhx-2 as an important modulator that extends reproductive longevity and ameliorates effects associated with alpha synuclein aggregation in C elegans.

scholarly journals Studies on C. elegans probed with estradiol, elucidate the critical role of Na+/H+ exchanger, nhx-2 in reproductive senescence and neuronal health

2020 ◽  
Author(s):  
Shikha Shukla ◽  
Lalit Kumar ◽  
Arunabh Sarkar ◽  
Kottapalli Srividya ◽  
Aamir Nazir
Keyword(s):  
Dietary Restriction ◽  
Histone H3 ◽  
Alpha Synuclein ◽  
Lysine Methylation ◽  
Estradiol Treatment ◽  
Reproductive Senescence ◽  
C Elegans ◽  
Histone H3 Acetylation ◽  
Alpha Synuclein Aggregation ◽  
H3 Acetylation

AbstractSetting in of reproductive senescence (RS) gives rise to several changes, making aged individuals susceptible to neurodegenerative diseases, cardiovascular and bone disorders amongst others. The present study deciphers the association of reproductive senescence, presence/absence of the sex hormone estradiol with age-associated neurodegenerative diseases. We employed RNAi induced silencing of a subset of 22 genes that are known to delay RS, followed by studies on alpha-Synuclein aggregation and associated effects in the transgenic C. elegans. These studies led us to fuctional characterisation of the Na+/H+ exchanger, expressed exclusively in gut. We found that RNAi of nhx-2 ameliorates the affects associated with alpha-Synuclein aggregation via mimicking dietary restriction as it alters food absorption from the gut. Our studies further elucidated that such effects are Sir-2.1 driven as nhx-2 RNAi did not delay reproductive senescence when sir-2.1 was silenced concurrently. As estradiol plays a central role in both reproductive health as well as neuronal health, we performed structural binding analysis that demonstrated the binding potential of the estradiol receptor NHR-14 with nhx-2 gene. Hence, we treated the worms with estradiol and observed that the transcription levels of nhx-2 were elevated above the endogenous level. To unravel the underlying molecular mechanism of induction we performed ChIP analysis and it revealed that estradiol treatment gives rise to enhanced NHX-2 levels through inducing the promoter specific histone H3 acetylation (H3K9) and lysine methylation (H3K4me3).Graphical abstractHIGHLIGHTSSilencing of a sodium proton antiporter nhx-2 of gut ameliorates effects associated with alpha-Synuclein aggregation via mimicking dietary restriction in C. elegans.We have established a genetic cross to construct a strain that expresses mCherry SIR-2.1 ubiquitously and α-Synuclein in muscles, that assists in corroborating the link between NHX-2 and SIR-2.1.Human 17-β-Estradiol treatment induces the expression of nhx-2, through inducing the promoter specific histone H3 acetylation (H3K9) and lysine methylation (H3K4me3).Effects associated with nhx-2, including prolonged reproductive span and neuroprotective effects, are SIR-2.1 driven.nhx-2 silencing decreases alpha-Synuclein aggregation however estradiol mediated overexpression above the endogenus level, does not amend the aggregation any further.

Analysis of alpha-synuclein aggregation and associated pathologies in a cellular model of multiple system atrophy

2005 ◽  
Vol 32 (06) ◽  
Author(s):  
G Fillon ◽  
M Neumann ◽  
R Zufferey ◽  
P Aebischer ◽  
HA Kretzschmar ◽  
...  
Keyword(s):  
Multiple System Atrophy ◽  
Alpha Synuclein ◽  
Cellular Model ◽  
Alpha Synuclein Aggregation

Functional characterization of the H+/K+ ATPase in wild type and gastrin knock-out mice

2007 ◽  
Vol 45 (05) ◽  
Author(s):  
A Schnur ◽  
P Hegyi ◽  
V Venglovecz ◽  
Z Rakonczay ◽  
I Ignáth ◽  
...  
Keyword(s):  
Functional Characterization ◽  
Wild Type ◽  
Knock Out ◽  
Knock Out Mice

scholarly journals Functional Characterization of the Adenylyl Cyclase Genesgs-1by Analysis of a Mutational Spectrum inCaenorhabditis elegans

Genetics ◽  
2002 ◽  
Vol 161 (1) ◽  
pp. 133-142 ◽  
Author(s):  
Celine Moorman ◽  
Ronald H A Plasterk
Keyword(s):  
Life Span ◽  
Adenylyl Cyclase ◽  
Neuronal Degeneration ◽  
Functional Characterization ◽  
Adenylyl Cyclases ◽  
Loss Of Function ◽  
C Elegans ◽  
Larval Stages ◽  
Pharyngeal Pumping

AbstractThe sgs-1 (suppressor of activated Gαs) gene encodes one of the four adenylyl cyclases in the nematode C. elegans and is most similar to mammalian adenylyl cyclase type IX. We isolated a complete loss-of-function mutation in sgs-1 and found it to result in animals with retarded development that arrest in variable larval stages. sgs-1 mutant animals exhibit lethargic movement and pharyngeal pumping and (while not reaching adulthood) have a mean life span that is >50% extended compared to wild type. An extensive set of reduction-of-function mutations in sgs-1 was isolated in a screen for suppressors of a neuronal degeneration phenotype induced by the expression of a constitutively active version of the heterotrimeric Gαs subunit of C. elegans. Although most of these mutations change conserved residues within the catalytic domains of sgs-1, mutations in the less-conserved transmembrane domains are also found. The sgs-1 reduction-of-function mutants are viable and have reduced locomotion rates, but do not show defects in pharyngeal pumping or life span.

scholarly journals Crosstalk between Different DNA Repair Pathways Contributes to Neurodegenerative Diseases

Biology ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 163
Author(s):  
Swapnil Gupta ◽  
Panpan You ◽  
Tanima SenGupta ◽  
Hilde Nilsen ◽  
Kulbhushan Sharma
Keyword(s):  
Dna Repair ◽  
Neurodegenerative Diseases ◽  
3D Models ◽  
Model Systems ◽  
Spinocerebellar Ataxias ◽  
C Elegans ◽  
Cellular Processes ◽  
Age Related ◽  
Damage Response ◽  
Lateral Sclerosis

Genomic integrity is maintained by DNA repair and the DNA damage response (DDR). Defects in certain DNA repair genes give rise to many rare progressive neurodegenerative diseases (NDDs), such as ocular motor ataxia, Huntington disease (HD), and spinocerebellar ataxias (SCA). Dysregulation or dysfunction of DDR is also proposed to contribute to more common NDDs, such as Parkinson’s disease (PD), Alzheimer’s disease (AD), and Amyotrophic Lateral Sclerosis (ALS). Here, we present mechanisms that link DDR with neurodegeneration in rare NDDs caused by defects in the DDR and discuss the relevance for more common age-related neurodegenerative diseases. Moreover, we highlight recent insight into the crosstalk between the DDR and other cellular processes known to be disturbed during NDDs. We compare the strengths and limitations of established model systems to model human NDDs, ranging from C. elegans and mouse models towards advanced stem cell-based 3D models.

scholarly journals TrkB neurotrophic activities are blocked by α-synuclein, triggering dopaminergic cell death in Parkinson’s disease

2017 ◽  
Vol 114 (40) ◽  
pp. 10773-10778 ◽  
Author(s):  
Seong Su Kang ◽  
Zhentao Zhang ◽  
Xia Liu ◽  
Fredric P. Manfredsson ◽  
Matthew J. Benskey ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neuronal Death ◽  
Kinase Domain ◽  
Alpha Synuclein ◽  
Mao B ◽  
Protein Levels ◽  
Trkb Receptors ◽  
Alpha Synuclein Aggregation ◽  
Neurotrophic Signaling

BDNF/TrkB neurotrophic signaling is essential for dopaminergic neuronal survival, and the activities are reduced in the substantial nigra (SN) of Parkinson’s disease (PD). However, whether α-Syn (alpha-synuclein) aggregation, a hallmark in the remaining SN neurons in PD, accounts for the neurotrophic inhibition remains elusive. Here we show that α-Syn selectively interacts with TrkB receptors and inhibits BDNF/TrkB signaling, leading to dopaminergic neuronal death. α-Syn binds to the kinase domain on TrkB, which is negatively regulated by BDNF or Fyn tyrosine kinase. Interestingly, α-Syn represses TrkB lipid raft distribution, decreases its internalization, and reduces its axonal trafficking. Moreover, α-Syn also reduces TrkB protein levels via up-regulation of TrkB ubiquitination. Remarkably, dopamine’s metabolite 3,4-Dihydroxyphenylacetaldehyde (DOPAL) stimulates the interaction between α-Syn and TrkB. Accordingly, MAO-B inhibitor rasagiline disrupts α-Syn/TrkB complex and rescues TrkB neurotrophic signaling, preventing α-Syn–induced dopaminergic neuronal death and restoring motor functions. Hence, our findings demonstrate a noble pathological role of α-Syn in antagonizing neurotrophic signaling, providing a molecular mechanism that accounts for its neurotoxicity in PD.

Sign in / Sign up

Export Citation Format

Share Document