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

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.

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

Journal of Experimental Medicine ◽

10.1084/jem.20160368 ◽

2016 ◽

Vol 213 (9) ◽

pp. 1759-1778 ◽

Cited By ~ 181

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.

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Cognitive and Physiological Substrates of Impaired Sentence Processing in Parkinson's Disease

Journal of Cognitive Neuroscience ◽

10.1162/jocn.1993.5.4.480 ◽

1993 ◽

Vol 5 (4) ◽

pp. 480-498 ◽

Cited By ~ 38

Author(s):

Murray Grossman ◽

Susan Carvell ◽

Stephen Gollomp ◽

Matthew B. Stern ◽

Martin Reivich ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Frontal Cortex ◽

Sentence Processing ◽

Sentence Comprehension ◽

Short Term Memory ◽

Brain Regions ◽

Positron Emission ◽

Left Caudate ◽

Regional Cerebral Glucose Metabolism

Sentence comprehension is a complex process involving at least a grammatical processor and a procedural component that supports language computations. One type of cerebral architecture that may underlie sentence processing is a network of distributed brain regions. We report two experiments designed to evaluate the cognitive and physiological substrate of sentence processing diaculties in nondemented patients with Parkinson's disease (PD). In the first experiment, patients answered simple questions about sentences that varied in their computational demands. Group and individual patient analyses indicated that PD patients are significantly compromised on this task, and that their difficulties become more prominent as the computational demands of the sentences increase. We manipulated the set of sentences to stress performance aspects of sentence processing. PD patients were compromised in their ability to detect errors in the presence and nature of a sentence's grammatical morphemes, suggesting a deficit in selective attention, but their ability to answer questions about a sentence was not afFected by short-term memory factors. In the second experiment, positron emission tomography was used to correlate this pattern of sentence comprehension impairment with regional cerebral glucose metabolism (rCMRgl) obtained at rest in a representative subset of these PD patients. Grammatical comprehension and attention in sentence processing correlated significantly with mesial frontal rCMRgl. Regression analyses confirmed the central role of left mesial frontal cortex, and identified a subsidiary role for left caudate in overall sentence comprehension, for left dorsolateral frontal cortex in grammatical processing, and for bilateral dorsolateral frontal cortex in attending to the presence of grammatical features. We conclude that compromised mesial frontal functioning underlies in part the sentence processing deficit of these patients, and these data illustrate one method for mapping portions of a sentence processing mechanism onto a distributed cerebral architecture.

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α-Synuclein E46K Mutation and Involvement of Oxidative Stress in a Drosophila Model of Parkinson’s Disease

Parkinson s Disease ◽

10.1155/2021/6621507 ◽

2021 ◽

Vol 2021 ◽

pp. 1-12

Author(s):

Samaneh Reiszadeh Jahromi ◽

S. R. Ramesh ◽

David I. Finkelstein ◽

Mohammad Haddadi

Keyword(s):

Oxidative Stress ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Gene Mutations ◽

Immunohistochemical Analysis ◽

Head Capsule ◽

Ethanol Sensitivity ◽

Wild Type ◽

Snca Gene ◽

Transgenic Flies

Parkinson’s disease (PD) is an age-associated neurodegenerative condition in which some genetic variants are known to increase disease susceptibility on interaction with environmental factors inducing oxidative stress. Different mutations in the SNCA gene are reported as the major genetic contributors to PD. E46K mutation pathogenicity has not been investigated as intensive as other SNCA gene mutations including A30P and A53T. In this study, based on the GAL4-UAS binary genetic tool, transgenic Drosophila melanogaster flies expressing wild-type and E46K-mutated copies of the human SNCA gene were constructed. Western blotting, immunohistochemical analysis, and light and confocal microscopy of flies’ brains were undertaken along with the survival rate measurement, locomotor function assay, and ethanol and paraquat (PQ) tolerance to study α-synuclein neurotoxicity. Biochemical bioassays were carried out to investigate the activity of antioxidant enzymes and alterations in levels of oxidative markers following damages induced by human α-synuclein to the neurons of the transgenic flies. Overexpression of human α-synuclein in the central nervous system of these transgenic flies led to disorganized ommatidia structures and loss of dopaminergic neurons. E46K α-synuclein caused remarkable climbing defects, reduced survivorship, higher ethanol sensitivity, and increased PQ-mediated mortality. A noticeable decline in activity of catalase and superoxide dismutase enzymes besides considerable increase in the levels of lipid peroxidation and reactive oxygen species was observed in head capsule homogenates of α-synuclein-expressing flies, which indicates obvious involvement of oxidative stress as a causal factor in SNCAE46K neurotoxicity. In all the investigations, E46K copy of the SNCA gene was found to impose more severe defects when compared to wild-type SNCA. It can be concluded that the constructed Drosophila models developed PD-like symptoms that facilitate comparative studies of molecular and cellular pathways implicated in the pathogenicity of different α-synuclein mutations.

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Evaluation of Markers of Oxidative Stress, Antioxidant Function and Astrocytic Proliferation in the Striatum and Frontal Cortex of Parkinson’s Disease Brains

Neurochemical Research ◽

10.1007/s11064-011-0471-9 ◽

2011 ◽

Vol 36 (8) ◽

pp. 1452-1463 ◽

Cited By ~ 80

Author(s):

Rajeswara Babu Mythri ◽

C. Venkateshappa ◽

G. Harish ◽

Anita Mahadevan ◽

Uday B. Muthane ◽

...

Keyword(s):

Oxidative Stress ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Frontal Cortex ◽

Antioxidant Function ◽

Markers Of Oxidative Stress

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Further Characterization of Intrastriatal Lipopolysaccharide Model of Parkinson’s Disease in C57BL/6 Mice

International Journal of Molecular Sciences ◽

10.3390/ijms22147380 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7380

Author(s):

Isaac Deng ◽

Frances Corrigan ◽

Sanjay Garg ◽

Xin-Fu Zhou ◽

Larisa Bobrovskaya

Keyword(s):

Oxidative Stress ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Olfactory Bulb ◽

Motor Impairment ◽

Distal Colon ◽

Post Treatment ◽

Synaptic Proteins ◽

Nigrostriatal Pathway ◽

Motor Impairments

Parkinson’s disease (PD) is the most common movement disorder, characterized by progressive degeneration of the nigrostriatal pathway, which consists of dopaminergic cell bodies in substantia nigra and their neuronal projections to the striatum. Moreover, PD is associated with an array of non-motor symptoms such as olfactory dysfunction, gastrointestinal dysfunction, impaired regulation of the sleep-wake cycle, anxiety, depression, and cognitive impairment. Inflammation and concomitant oxidative stress are crucial in the pathogenesis of PD. Thus, this study aimed to model PD via intrastriatal injection of the inflammagen lipopolysaccharide (LPS)to investigate if the lesion causes olfactory and motor impairments, inflammation, oxidative stress, and alteration in synaptic proteins in the olfactory bulb, striatum, and colon. Ten µg of LPS was injected unilaterally into the striatum of 27 male C57BL/6 mice, and behavioural assessment was conducted at 4 and 8 weeks post-treatment, followed by tissue collection. Intrastriatal LPS induced motor impairment in C57BL/6 mice at 8 weeks post-treatment evidenced by reduced latency time in the rotarod test. LPS also induced inflammation in the striatum characterized by increased expression of microglial marker Iba-1 and astrocytic marker GFAP, with degeneration of dopaminergic neuronal fibres (reduced tyrosine hydroxylase immunoreactivity), and reduction of synaptic proteins andDJ-1 protein. Additionally, intrastriatal LPS induced inflammation, oxidative stress and alterations in synaptic proteins within the olfactory bulb, although this did not induce a significant impairment in olfactory function. Intrastriatal LPS induced mild inflammatory changes in the distal colon, accompanied by increased protein expression of 3-nitrotyrosine-modified proteins. This model recapitulated the major features of PD such as motor impairment and degeneration of dopaminergic neuronal fibres in the striatum, as well as some pathological changes in the olfactory bulb and colon; thus, this model could be suitable for understanding clinical PD and testing neuroprotective strategies.

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

10.1101/2020.02.27.968545 ◽

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.

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

Toxicological Sciences ◽

10.1093/toxsci/kfaa183 ◽

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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