Gut bacterial composition in a mouse model of Parkinson’s disease

2018 ◽  
Vol 9 (5) ◽  
pp. 799-814 ◽  
Author(s):  
P. Perez-Pardo ◽  
H.B. Dodiya ◽  
P.A. Engen ◽  
A. Naqib ◽  
C.B. Forsyth ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mouse Model ◽  
Intestinal Inflammation ◽  
Alpha Synuclein ◽  
Enteric Neurons ◽  
Intestinal Epithelial ◽  
Bacterial Composition ◽  
Alpha Synuclein Aggregation ◽  
First Time

The mechanism of neurodegeneration in Parkinson’s disease (PD) remains unknown but it has been hypothesised that the intestinal tract could be an initiating and contributing factor to the neurodegenerative processes. In PD patients as well as in animal models for PD, alpha-synuclein-positive enteric neurons in the colon and evidence of colonic inflammation have been demonstrated. Moreover, several studies reported pro-inflammatory bacterial dysbiosis in PD patients. Here, we report for the first time significant changes in the composition of caecum mucosal associated and luminal microbiota and the associated metabolic pathways in a rotenone-induced mouse model for PD. The mouse model for PD, induced by the pesticide rotenone, is associated with an imbalance in the gut microbiota, characterised by a significant decrease in the relative abundance of the beneficial commensal bacteria genus Bifidobacterium. Overall, intestinal bacterial dysbiosis might play an important role in both the disruption of intestinal epithelial integrity and intestinal inflammation, which could lead or contribute to the observed alpha-synuclein aggregation and PD pathology in the intestine and central nervous system in the oral rotenone mouse model of PD.

scholarly journals ATH434 Reverses Colorectal Dysfunction in the A53T Mouse Model of Parkinson’s Disease

2021 ◽  
pp. 1-12
Author(s):  
Shanti Diwakarla ◽  
Rachel M. McQuade ◽  
Remy Constable ◽  
Olivia Artaiz ◽  
Enie Lei ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mouse Model ◽  
Iron Chelator ◽  
Alpha Synuclein ◽  
Enteric Neurons ◽  
Potential Clinical Benefit ◽  
Enteric Neuropathy ◽  
Orally Bioavailable

Background: Gastrointestinal (GI) complications, that severely impact patient quality of life, are a common occurrence in patients with Parkinson’s disease (PD). Damage to enteric neurons and the accumulation of alpha-synuclein in the enteric nervous system (ENS) are thought to contribute to this phenotype. Copper or iron chelators, that bind excess or labile metal ions, can prevent aggregation of alpha-synuclein in the brain and alleviate motor-symptoms in preclinical models of PD. Objective: We investigated the effect of ATH434 (formally PBT434), a small molecule, orally bioavailable, moderate-affinity iron chelator, on colonic propulsion and whole gut transit in A53T alpha-synuclein transgenic mice. Methods: Mice were fed ATH434 (30 mg/kg/day) for either 4 months (beginning at ∼15 months of age), after the onset of slowed propulsion (“treatment group”), or for 3 months (beginning at ∼12 months of age), prior to slowed propulsion (“prevention group”). Results: ATH434, given after dysfunction was established, resulted in a reversal of slowed colonic propulsion and gut transit deficits in A53T mice to WT levels. In addition, ATH434 administered from 12 months prevented the slowed bead expulsion at 15 months but did not alter deficits in gut transit time when compared to vehicle-treated A53T mice. The proportion of neurons with nuclear Hu+ translocation, an indicator of neuronal stress in the ENS, was significantly greater in A53T than WT mice, and was reduced in both groups when ATH434 was administered. Conclusion: ATH434 can reverse some of the GI deficits and enteric neuropathy that occur in a mouse model of PD, and thus may have potential clinical benefit in alleviating the GI dysfunctions associated with PD.

Lysosomal malfunction accompanies alpha-synuclein aggregation in a progressive mouse model of Parkinson’s disease

2002 ◽  
Vol 956 (1) ◽  
pp. 156-165 ◽  
Author(s):  
G.E Meredith ◽  
S Totterdell ◽  
E Petroske ◽  
K Santa Cruz ◽  
R.C Callison ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mouse Model ◽  
Alpha Synuclein ◽  
Alpha Synuclein Aggregation

scholarly journals Presynaptic Alpha-Synuclein Aggregation in a Mouse Model of Parkinson's Disease

2014 ◽  
Vol 34 (6) ◽  
pp. 2037-2050 ◽  
Author(s):  
K. J. Spinelli ◽  
J. K. Taylor ◽  
V. R. Osterberg ◽  
M. J. Churchill ◽  
E. Pollock ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mouse Model ◽  
Alpha Synuclein ◽  
Alpha Synuclein Aggregation

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.

scholarly journals Mitochondrial Dysfunction: The Road to Alpha-Synuclein Oligomerization in PD

2011 ◽  
Vol 2011 ◽  
pp. 1-20 ◽  
Author(s):  
A. R. Esteves ◽  
D. M. Arduíno ◽  
D. F. F. Silva ◽  
C. R. Oliveira ◽  
S. M. Cardoso
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Dysfunction ◽  
Neuronal Cell ◽  
Alpha Synuclein ◽  
Vital Role ◽  
Microtubule Network ◽  
The Road ◽  
Species Production ◽  
Alpha Synuclein Aggregation

While the etiology of Parkinson's disease remains largely elusive, there is accumulating evidence suggesting that mitochondrial dysfunction occurs prior to the onset of symptoms in Parkinson's disease. Mitochondria are remarkably primed to play a vital role in neuronal cell survival since they are key regulators of energy metabolism (as ATP producers), of intracellular calcium homeostasis, of NAD+/NADH ratio, and of endogenous reactive oxygen species production and programmed cell death. In this paper, we focus on mitochondrial dysfunction-mediated alpha-synuclein aggregation. We highlight some of the findings that provide proof of evidence for a mitochondrial metabolism control in Parkinson's disease, namely, mitochondrial regulation of microtubule-dependent cellular traffic and autophagic lysosomal pathway. The knowledge that microtubule alterations may lead to autophagic deficiency and may compromise the cellular degradation mechanisms that culminate in the progressive accumulation of aberrant protein aggregates shields new insights to the way we address Parkinson's disease. In line with this knowledge, an innovative window for new therapeutic strategies aimed to restore microtubule network may be unlocked.

scholarly journals Serotonergic dysfunction in the A53T alpha-synuclein mouse model of Parkinson's disease

2015 ◽  
Vol 135 (3) ◽  
pp. 589-597 ◽  
Author(s):  
Janina Deusser ◽  
Stefanie Schmidt ◽  
Benjamin Ettle ◽  
Sonja Plötz ◽  
Sabine Huber ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mouse Model ◽  
Alpha Synuclein ◽  
Serotonergic Dysfunction
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