scholarly journals Widespread transneuronal propagation of α-synucleinopathy triggered in olfactory bulb mimics prodromal Parkinson’s disease

2016 ◽  
Vol 213 (9) ◽  
pp. 1759-1778 ◽  
Author(s):  
Nolwen L. Rey ◽  
Jennifer A. Steiner ◽  
Nazia Maroof ◽  
Kelvin C. Luk ◽  
Zachary Madaj ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mouse Model ◽  
Olfactory Bulb ◽  
Amyloid Fibrils ◽  
Brain Regions ◽  
Neural Pathways ◽  
Wild Type

Parkinson’s disease (PD) is characterized by the progressive appearance of intraneuronal Lewy aggregates, which are primarily composed of misfolded α-synuclein (α-syn). The aggregates are believed to propagate via neural pathways following a stereotypical pattern, starting in the olfactory bulb (OB) and gut. We hypothesized that injection of fibrillar α-syn into the OB of wild-type mice would recreate the sequential progression of Lewy-like pathology, while triggering olfactory deficits. We demonstrate that injected α-syn fibrils recruit endogenous α-syn into pathological aggregates that spread transneuronally over several months, initially in the olfactory network and later in distant brain regions. The seeded inclusions contain posttranslationally modified α-syn that is Thioflavin S positive, indicative of amyloid fibrils. The spreading α-syn pathology induces progressive and specific olfactory deficits. Thus, we demonstrate that propagating α-syn pathology triggered in the OB is functionally detrimental. Collectively, we have created a mouse model of prodromal PD.

scholarly journals Environmental Enrichment Attenuates Oxidative Stress and Alters Detoxifying Enzymes in an A53T α-Synuclein Transgenic Mouse Model of Parkinson’s Disease

Antioxidants ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 928
Author(s):  
Jung Hwa Seo ◽  
Seong-Woong Kang ◽  
Kyungri Kim ◽  
Soohyun Wi ◽  
Jang Woo Lee ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Olfactory Bulb ◽  
Frontal Cortex ◽  
Brain Stem ◽  
Environmental Enrichment ◽  
Brain Regions ◽  
Wild Type ◽  
Detoxifying Enzymes

Although environmental enrichment (EE) is known to reduce oxidative stress in Parkinson’s disease (PD), the metabolic alternations for detoxifying endogenous and xenobiotic compounds according to various brain regions are not fully elucidated yet. This study aimed to further understand the role of EE on detoxifying enzymes, especially those participating in phase I of metabolism, by investigating the levels of enzymes in various brain regions such as the olfactory bulb, brain stem, frontal cortex, and striatum. Eight-month-old transgenic PD mice with the overexpression of human A53T α-synuclein and wild-type mice were randomly allocated to either standard cage condition or EE for 2 months. At 10 months of age, the expression of detoxifying enzymes was evaluated and compared with wild-type of the same age raised in standard cages. EE improved neurobehavioral outcomes such as olfactory and motor function in PD mice. EE-treated mice showed that oxidative stress was attenuated in the olfactory bulb, brain stem, and frontal cortex. EE also reduced apoptosis and induced cell proliferation in the subventricular zone of PD mice. The overexpression of detoxifying enzymes was observed in the olfactory bulb and brain stem of PD mice, which was ameliorated by EE. These findings were not apparent in the other experimental regions. These results suggest the stage of PD pathogenesis may differ according to brain region, and that EE has a protective effect on the PD pathogenesis by decreasing oxidative stress.

scholarly journals A Guide to the Generation of a 6-Hydroxydopamine Mouse Model of Parkinson’s Disease for the Study of Non-Motor Symptoms

Biomedicines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 598
Author(s):  
Débora Masini ◽  
Carina Plewnia ◽  
Maëlle Bertho ◽  
Nicolas Scalbert ◽  
Vittorio Caggiano ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mouse Model ◽  
Survival Rates ◽  
Dorsal Striatum ◽  
Brain Regions ◽  
Motor Symptoms ◽  
Operative Care ◽  
6 Hydroxydopamine ◽  
Non Motor Symptoms

In Parkinson’s disease (PD), a large number of symptoms affecting the peripheral and central nervous system precede, develop in parallel to, the cardinal motor symptoms of the disease. The study of these conditions, which are often refractory to and may even be exacerbated by standard dopamine replacement therapies, relies on the availability of appropriate animal models. Previous work in rodents showed that injection of the neurotoxin 6-hydroxydopamine (6-OHDA) in discrete brain regions reproduces several non-motor comorbidities commonly associated with PD, including cognitive deficits, depression, anxiety, as well as disruption of olfactory discrimination and circadian rhythm. However, the use of 6-OHDA is frequently associated with significant post-surgical mortality. Here, we describe the generation of a mouse model of PD based on bilateral injection of 6-OHDA in the dorsal striatum. We show that the survival rates of males and females subjected to this lesion differ significantly, with a much higher mortality among males, and provide a protocol of enhanced pre- and post-operative care, which nearly eliminates animal loss. We also briefly discuss the utility of this model for the study of non-motor comorbidities of PD.

scholarly journals Selenotranscriptomic Analyses Identify Signature Selenoproteins in Brain Regions in a Mouse Model of Parkinson’s Disease

PLoS ONE ◽  
2016 ◽  
Vol 11 (9) ◽  
pp. e0163372 ◽  
Author(s):  
Xiong Zhang ◽  
Yang-Lie Ye ◽  
Hui Zhu ◽  
Sheng-Nan Sun ◽  
Jing Zheng ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mouse Model ◽  
Brain Regions

scholarly journals Cryo-EM structures of α-synuclein fibrils with the H50Q hereditary mutation reveal new polymorphs

2019 ◽  
Author(s):  
David R. Boyer ◽  
Binsen Li ◽  
Chuanqi Sun ◽  
Weijia Fan ◽  
Michael R. Sawaya ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Hydrogen Bond ◽  
Parkinson's Disease ◽  
Dementia With Lewy Bodies ◽  
Amyloid Fibrils ◽  
Lewy Bodies ◽  
Wild Type ◽  
In The Wild ◽  
Bond Network ◽  
Intramolecular Hydrogen

AbstractDeposits of amyloid fibrils of α-synuclein are the histological hallmarks of Parkinson’s disease, multiple system atrophy, and dementia with Lewy bodies. Although most cases of these diseases are sporadic, autosomal-dominant hereditary mutations have been linked to Parkinson’s disease and dementia with Lewy bodies. Seeing the changes to the structure of amyloid fibrils bearing these mutations may help to understand these diseases. To this end, we determined the cryo-EM structures of α-synuclein fibrils containing the H50Q hereditary mutation. We find that the H50Q mutation results in two new polymorphs of α-synuclein, which we term Narrow and Wide Fibrils. Both polymorphs recapitulate the conserved kernel formed by residues 50-77 observed in wild-type structures; however, the Narrow and Wide Fibrils reveal that H50Q disrupts a key interaction between H50-E57 on the opposing protofilament, abolishing the extensive protofilament interface formed by preNAC residues in the wild-type “rod” structure. Instead, the Narrow Fibril is formed from a single protofilament and the two protofilaments of the Wide protofilament are held together by only a pair of atoms – the Cɣ atoms from the two threonine 59 sidechains. Further, we find that H50Q forms an intramolecular hydrogen bond with K45 leading to the formation of a novel β-arch formed by residues 36-46 that features an extensive hydrogen-bond network between Y39, T44, and E46. The structures of the H50Q polymorphs help to rationalize the faster aggregation kinetics, higher seeding capacity in biosensor cells, and greater cytotoxicity we observe for H50Q compared to wild-type α-synuclein.

P166 Modulation of adult neurogenesis in the olfactory bulb in an acute mouse model of Parkinson’s disease

Basal Ganglia ◽  
2011 ◽  
Vol 1 (1) ◽  
pp. 41
Author(s):  
W. Chiu ◽  
T. Carlsson ◽  
M. Arend ◽  
W.H. Oertel ◽  
G. Höglinger ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mouse Model ◽  
Olfactory Bulb ◽  
Adult Neurogenesis

scholarly journals Transcriptomic Profiling of Circular RNA in Different Brain Regions of Parkinson’s Disease in a Mouse Model

2020 ◽  
Vol 21 (8) ◽  
pp. 3006 ◽  
Author(s):  
Erteng Jia ◽  
Ying Zhou ◽  
Zhiyu Liu ◽  
Liujing Wang ◽  
Tinglan Ouyang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mouse Model ◽  
Signaling Pathway ◽  
Target Genes ◽  
Kegg Pathway ◽  
Brain Regions ◽  
Differentially Expressed ◽  
Sequencing Analysis ◽  
Qrt Pcr

Parkinson’s disease (PD) is the second most common neurodegenerative disease and although many studies have been done on this disease, the underlying mechanisms are still poorly understood and further studies are warranted. Therefore, this study identified circRNA expression profiles in the cerebral cortex (CC), hippocampus (HP), striatum (ST), and cerebellum (CB) regions of the 1-methyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model using RNA sequencing (RNA-seq), and differentially expressed circRNA were validated using reverse transcription quantitative real-time PCR (qRT-PCR). Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and competing endogenous RNA (ceRNA) network analyses were also performed to explore the potential function of circRNAs. The results show that, compared with the control group, 24, 66, 71, and 121 differentially expressed circRNAs (DE-circRNAs) were found in the CC, HP, ST, and CB, respectively. PDST vs. PDCB, PDST vs. PDHP, and PDCB vs. PDHP groups have 578, 110, and 749 DE-circRNAs, respectively. Then, seven DE-cirRNAs were selected for qRT-PCR verification, where the expressions were consistent with the sequencing analysis. The GO and KEGG pathway analyses revealed that these DE-circRNAs participate in several biological functions and signaling pathways, including glutamic synapse, neuron to neuron synapse, cell morphogenesis involved in neuron differentiation, Parkinson’s disease, axon guidance, cGMP-PKG signaling pathway, and PI3K-Akt signaling pathway. Furthermore, the KEGG analysis of the target genes predicted by DE-circRNAs indicated that the target genes predicted by mmu_circRNA_0003292, mmu_circRNA_0001320, mmu_circRNA_0005976, and mmu_circRNA_0005388 were involved in the PD-related pathway. Overall, this is the first study on the expression profile of circRNAs in the different brain regions of PD mouse model. These results might facilitate our understanding of the potential roles of circRNAs in the pathogenesis of PD. Moreover, the results also indicate that the mmu_circRNA_0003292-miRNA-132-Nr4a2 pathway might be involved in the regulation of the molecular mechanism of Parkinson’s disease.

Selegiline and L-DOPA modulate the number of newborn neurons in the olfactory bulb in an acute 6-OHDA mouse model of Parkinson's disease

Basal Ganglia ◽  
2013 ◽  
Vol 3 (1) ◽  
pp. 45
Author(s):  
W. Chiu ◽  
T. Carlsson ◽  
C. Depboylu ◽  
W.H. Oertel ◽  
G. Höglinger ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mouse Model ◽  
Olfactory Bulb ◽  
Newborn Neurons

scholarly journals Deficits in olfactory sensitivity in a mouse model of Parkinson’s disease revealed by plethysmography of odor-evoked sniffing

2020 ◽  
Author(s):  
Michaela E. Johnson ◽  
Liza Bergkvist ◽  
Gabriela Mercado ◽  
Lucas Stetzik ◽  
Lindsay Meyerdirk ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Olfactory Bulb ◽  
Brain Regions ◽  
Detection Sensitivity ◽  
Motor Nucleus ◽  
List Type ◽  
Anterior Olfactory Nucleus ◽  
Odor Detection ◽  
Female Mice

AbstractHyposmia is evident in over 90% of Parkinson’s disease (PD) patients. A characteristic of PD is intraneuronal deposits composed in part of α-synuclein fibrils. Based on the analysis of post-mortem PD patients, Braak and colleagues suggested that early in the disease α-synuclein pathology is present in the dorsal motor nucleus of the vagus, as well as the olfactory bulb and the anterior olfactory nucleus, and then later affects other interconnected brain regions. Here, we bilaterally injected α-synuclein preformed fibrils into the olfactory bulb of wild type male and female mice. Six-months after injection, the anterior olfactory nucleus and the piriform cortex displayed a high α-synuclein pathology load. We evaluated olfactory perceptual function by monitoring odor-evoked sniffing behavior in a plethysmograph at one-, three- and six-months after injection of α-synuclein fibrils. At all-time points, females injected with fibrils exhibited reduced odor detection sensitivity, which was detectable with the semi-automated plethysmography apparatus, but not a buried pellet test. In future studies, this sensitive methodology we used to assess olfactory detection deficits could be used to define how α-synuclein pathology affects other aspects of olfactory perception in PD models and to clarify the neuropathological underpinnings of these deficits.Highlights- α-synuclein pathology spreads through neuronally-connected areas after bilateral injection of preformed fibrils into the olfactory bulb.- A plethysmograph and an olfactometer were used for a semi-automated screen of odor-evoked sniffing as an assay for odor detection sensitivity.- Bilateral olfactory bulb injections of α-synuclein preformed fibrils in female mice led to reduced sensitivity for detecting odors.- The semi-automated plethysmography apparatus was more sensitive at detecting odor detection deficits than the buried pellet test.

Selegiline normalizes, while l-DOPA sustains the increased number of dopamine neurons in the olfactory bulb in a 6-OHDA mouse model of Parkinson's disease

2014 ◽  
Vol 79 ◽  
pp. 212-221 ◽  
Author(s):  
Wei-Hua Chiu ◽  
Thomas Carlsson ◽  
Candan Depboylu ◽  
Günter U. Höglinger ◽  
Wolfgang H. Oertel ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mouse Model ◽  
Olfactory Bulb ◽  
Dopamine Neurons

scholarly journals Paraquat Inhalation, a Translationally Relevant Route of Exposure: Disposition to the Brain and Male-Specific Olfactory Impairment in Mice

2020 ◽  
Author(s):  
Timothy Anderson ◽  
Alyssa K Merrill ◽  
Matthew L Eckard ◽  
Elena Marvin ◽  
Katherine Conrad ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Olfactory Bulb ◽  
Brain Regions ◽  
Olfactory Discrimination ◽  
Olfactory Impairment ◽  
Route Of Exposure ◽  
Male Specific ◽  
The Brain ◽  
Lung And Kidney

Abstract Epidemiological and experimental studies have associated oral and systemic exposures to the herbicide paraquat (PQ) with Parkinson’s disease. Despite recognition that airborne particles and solutes can be directly translocated to the brain via olfactory neurons, the potential for inhaled PQ to cause olfactory impairment has not been investigated. This study sought to determine if prolonged low-dose inhalation exposure to PQ would lead to disposition to the brain and olfactory impairment, a prodromal feature of Parkinson’s disease. Adult male and female C57BL/6J mice were exposed to PQ aerosols in a whole-body inhalation chamber for 4 h/day, 5 days/week for 4 weeks. Subsets of mice were sacrificed during and after exposure and PQ concentrations in various brain regions (olfactory bulb, striatum, midbrain, and cerebellum) lung, and kidney were quantified via mass spectrometry. Alterations in olfaction were examined using an olfactory discrimination paradigm. PQ inhalation resulted in an appreciable burden in all examined brain regions, with the highest burden observed in the olfactory bulb, consistent with nasal olfactory uptake. PQ was also detected in the lung and kidney, yet PQ levels in all tissues returned to control values within 4 weeks post exposure. PQ inhalation caused persistent male-specific deficits in olfactory discrimination. No effects were observed in females. These data support the importance of route of exposure in determination of safety estimates for neurotoxic pesticides, such as PQ. Accurate estimation of the relationship between exposure and internal dose is critical for risk assessment and public health protection.

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