Defining α-synuclein species responsible for Parkinson's disease phenotypes in mice.
DOPAMINERGIC neurons; FOURIER transform infrared spectroscopy; MOUSE diseases; PARKINSON'S disease; SPECIES; SUBSTANTIA nigra
Parkinson's disease (PD) is a neurodegenerative disorder characterized by fibrillar neuronal inclusions composed of aggregatedβ-synuclein (β-syn). These inclusions are associated with behavioral and pathological PD phenotypes. One strategy for therapeutic interventions is to prevent the formation of these inclusions to halt disease progression. β-Synuclein exists in multiple structural forms, including disordered, nonamyloid oligomers, ordered amyloid oligomers, and fibrils. It is critical to understand which conformers contribute to specific PD phenotypes. Here, we utilized a mouse model to explore the pathological effects of stable α-amyloid-sheet oligomers compared with those of fibrillar β-synuclein. We biophysically characterized these species with transmission EM, atomic-force microscopy, CD spectroscopy, FTIR spectroscopy, analytical ultracentrifugation, and thioflavin T assays. We then injected these different β-synuclein forms into the mouse striatum to determine their ability to induce PD-related phenotypes. We found thatα-sheet oligomers produce a small but significant loss of dopamine neurons in the substantia nigra pars compacta (SNc). Injection of small α-sheet fibril fragments, however, produced the most robust phenotypes, including reduction of striatal dopamine terminals, SNc loss of dopamine neurons, and motor-behavior defects. We conclude that although theα-sheet oligomers cause some toxicity, the potent effects of the short fibrillar fragments can be attributed to their ability to recruit monomeric β-synuclein and spread in vivo and hence contribute to the development of PD-like phenotypes. These results suggest that strategies to reduce the formation and propagation ofα-sheet fibrillar species could be an important route for therapeutic intervention in PD and related disorders. [ABSTRACT FROM AUTHOR]
Froula Jessica M; Castellana-Cruz Marta; Anabtawi Nadia M; Camino José D; Chen Serene W; Thrasher Drake R; Freire Jennifer; Yazdi Allen A; Fleming Sheila; Dobson Christopher M; Kumita Janet R; Cremades Nunilo; Volpicelli-Daley Laura A
Journal of Biological Chemistry
2019
2019-07
<a href="http://doi.org/10.1074/jbc.ra119.007743" target="_blank" rel="noreferrer noopener">10.1074/jbc.ra119.007743</a>
Developmental exposure to the organochlorine pesticide dieldrin causes male-specific exacerbation of α-synuclein-preformed fibril-induced toxicity and motor deficits.
Sex differences; Neuroinflammation; Parkinson's; Neurotoxicity; Pesticide; PARKINSON'S disease; SUBSTANTIA nigra; Synuclein; CORN oil; ORGANOCHLORINE pesticides; SALINE injections
Human and animal studies have shown that exposure to the organochlorine pesticide dieldrin is associated with increased risk of Parkinson's disease (PD). Previous work showed that developmental dieldrin exposure increased neuronal susceptibility to MPTP toxicity in male C57BL/6 mice, possibly via changes in dopamine (DA) packaging and turnover. However, the relevance of the MPTP model to PD pathophysiology has been questioned. We therefore studied dieldrin-induced neurotoxicity in the α-synuclein (α-syn)-preformed fibril (PFF) model, which better reflects the α-syn pathology and toxicity observed in PD pathogenesis. Specifically, we used a "two-hit" model to determine whether developmental dieldrin exposure increases susceptibility to α-syn PFF-induced synucleinopathy. Dams were fed either dieldrin (0.3 mg/kg, every 3–4 days) or vehicle corn oil starting 1 month prior to breeding and continuing through weaning of pups at postnatal day 22. At 12 weeks of age, male and female offspring received intrastriatal α-syn PFF or control saline injections. Consistent with the male-specific increased susceptibility to MPTP, our results demonstrate that developmental dieldrin exposure exacerbates PFF-induced toxicity in male mice only. Specifically, in male offspring, dieldrin exacerbated PFF-induced motor deficits on the challenging beam and increased DA turnover in the striatum 6 months after PFF injection. However, male offspring showed neither exacerbation of phosphorylated α-syn aggregation (pSyn) in the substantia nigra (SN) at 1 or 2 months post-PFF injection, nor exacerbation of PFF-induced TH and NeuN loss in the SN 6 months post-PFF injection. Collectively, these data indicate that developmental dieldrin exposure produces a male-specific exacerbation of synucleinopathy-induced behavioral and biochemical deficits. This sex-specific result is consistent with both previous work in the MPTP model, our previously reported sex-specific effects of this exposure paradigm on the male and female epigenome, and the higher prevalence and more severe course of PD in males. The novel two-hit environmental toxicant/PFF exposure paradigm established in this project can be used to explore the mechanisms by which other PD-related exposures alter neuronal vulnerability to synucleinopathy in sporadic PD. Unlabelled Image • Developmental dieldrin exposure increases α- syn -PFF-induced motor deficits. • Developmental dieldrin exposure increases PFF-induced deficits in DA handling. • Developmental dieldrin exposure does not affect PFF-induced loss of nigral neurons. • This is a novel paradigm modeling how environmental factors increase risk of PD. • Female mice show PFF-induced pathology, but no PFF-induced motor deficits. [ABSTRACT FROM AUTHOR]
Gezer AO; Kochmanski J; VanOeveren SE; Cole-Strauss A; Kemp CJ; Patterson JR; Miller KM; Kuhn NC; Herman DE; McIntire A; Lipton JW; Luk KC; Fleming SM; Sortwell CE; Bernstein AI
Neurobiology of Disease
2020
2020-07-15
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.1016/j.nbd.2020.104947" target="_blank" rel="noreferrer noopener">10.1016/j.nbd.2020.104947</a>
Estrogen And Parkinson's Disease
alpha-synuclein gene; antiphospholipid antibodies; brain dopamine; dopamine; female rats; gender differences; nigrostriatal dopaminergic system; oral-contraceptives; postmenopausal women; sex-differences; striatal
Horstink Mwim; Strijks E; Dluzen D E
Parkinson's Disease
2003
2003
Book Chapter
n/a
Evidence of Oropharyngeal Dysfunction in Feeding in the Rat Rotenone Model of Parkinson's Disease.
Animal Studies; Deglutition – Drug Effects; Deglutition Disorders; Eating – Drug Effects; Feeding Methods; Isoflavones – Administration and Dosage; Isoflavones – Pharmacodynamics; Mastication; Oropharynx – Pathology; Parkinson Disease; Phenotype; Rats
Swallowing disorders in Parkinson's disease are not responsive to dopamine depletion therapy and contribute to morbidity. They are poorly understood owing to a lack of adequate models. We present the first evidence of oropharyngeal changes in a rotenone toxicity model of Parkinson's disease. Rats were recorded while feeding before and after daily rotenone injections at two different doses (2.75 mg/kg and 3 mg/kg). The higher dose had a much more severe parkinsonian phenotype than the low dose. Timing and amplitude of chewing changed, as did the coordination of chewing and swallowing. Dose-dependent effects were evident. These preliminary results indicate that future research in toxicological models of Parkinson's disease should incorporate the study of oropharyngeal dysfunction. A better understanding of nongenetic models of Parkinson's disease in feeding may open new avenues for research into the neurological and behavioral bases for swallowing dysfunction in Parkinson's disease.
Gould Francois D H; Gross Andrew; German Rebecca Z; Richardson Jason R
Parkinson's disease
2018
1905-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1155/2018/6537072" target="_blank" rel="noreferrer noopener">10.1155/2018/6537072</a>
Pharmacological inhibition of CSF1R by GW2580 reduces microglial proliferation and is protective against neuroinflammation and dopaminergic neurodegeneration.
microglia; neuroprotection; Parkinson's disease; proliferation
Increased pro‐inflammatory cytokine levels and proliferation of activated microglia have been found in Parkinson's disease (PD) patients and animal models of PD, suggesting that targeting of the microglial inflammatory response may result in neuroprotection in PD. Microglial proliferation is regulated by many factors, but colony stimulating factor‐1 receptor (CSF1R) has emerged as a primary factor. Using data mining techniques on existing microarray data, we found that mRNA expression of the CSF1R ligand, CSF‐1, is increased in the brain of PD patients compared to controls. In two different neurotoxic mouse models of PD, acute MPTP and sub‐chronic LPS treatment, mRNA and protein levels of CSF1R and CSF‐1 were significantly increased. Treatment with the CSF1R inhibitor GW2580 significantly attenuated MPTP‐induced CSF1R activation and Iba1‐positive cell proliferation, without a reduction of the basal Iba1‐positive population in the substantia nigra. GW2580 treatment also significantly decreased mRNA levels of pro‐inflammatory factors, without alteration of anti‐inflammatory mediators, and significantly attenuated the MPTP‐induced loss of dopamine neurons and motor behavioral deficits. Importantly, these effects were observed in the absence of overt microglial depletion, suggesting that targeting CSF1R signaling may be a viable neuroprotective strategy in PD that disrupts pro‐inflammatory signaling, but maintains the beneficial effects of microglia. [ABSTRACT FROM AUTHOR]
Neal Matthew L; Fleming Sheila M; Budge Kevin M; Boyle Alexa M; Kim Chunki; Alam Gelareh; Beier Eric E; Wu Long‐Jun; Richardson Jason R
FASEB Journal
2020
2020-01
Journal Article
<a href="http://doi.org/10.1096/fj.201900567RR" target="_blank" rel="noreferrer noopener">10.1096/fj.201900567RR</a>
Role of rodent models in advancing precision medicine for Parkinson's disease
With a current lack of disease-modifying treatments, an initiative toward implementing a precision medicine approach for treating Parkinson's disease (PD) has emerged. However, challenges remain in how to define and apply precision medicine in PD. To accomplish the goal of optimally targeted and timed treatment for each patient, preclinical research in a diverse population of rodent models will continue to be an essential part of the translational path to identify novel biomarkers for patient diagnosis and subgrouping, understand PD disease mechanisms, identify new therapeutic targets, and screen therapeutics prior to clinical testing. This review highlights the most common rodent models of PD and discusses how these models can contribute to defining and implementing precision medicine for the treatment of PD.
Emily Simons
Sheila M Fleming
Handb Clin Neurol
. 2023;193:3-16.
2023
English
Targeting alpha-synuclein via the immune system in Parkinson's disease: Current vaccine therapies
Parkinson's disease (PD) is the second most common neurodegenerative disorder and is defined pathologically by the abnormal accumulation of the presynaptic protein alpha-synuclein (aSyn) in the form of Lewy bodies and Lewy neurites and loss of midbrain dopaminergic neurons in the substantia nigra pars compacta. Because of aSyn's involvement in both sporadic and familial forms of PD, it has become a key target for the development of novel therapeutics. Aberrant aSyn is associated with multiple mechanisms of neuronal dysfunction and degeneration including inflammation, impaired mitochondrial function, altered protein degradation systems, and oxidative stress. Inflammation, in particular, has emerged as a potential significant contributor early in the disease making it an attractive target for disease modification and neuroprotection. Thus, immunotherapies targeting aSyn are currently being investigated in pre-clinical and clinical trials. The focus of this review is to highlight the role of aSyn in neuroinflammation and discuss the current status of aSyn-directed immunotherapies in pre-clinical and clinical trials for PD.
Sheila M Fleming
Ashley Davis
Emily Simons
Neuropharmacology
. 2022 Jan 1;202:108870. doi: 10.1016/j.neuropharm.2021.108870. Epub 2021 Nov 3.
2022
English
Targeting alpha-synuclein via the immune system in Parkinson's disease: Current vaccine therapies
Parkinson's disease (PD) is the second most common neurodegenerative disorder and is defined pathologically by the abnormal accumulation of the presynaptic protein alpha-synuclein (aSyn) in the form of Lewy bodies and Lewy neurites and loss of midbrain dopaminergic neurons in the substantia nigra pars compacta. Because of aSyn's involvement in both sporadic and familial forms of PD, it has become a key target for the development of novel therapeutics. Aberrant aSyn is associated with multiple mechanisms of neuronal dysfunction and degeneration including inflammation, impaired mitochondrial function, altered protein degradation systems, and oxidative stress. Inflammation, in particular, has emerged as a potential significant contributor early in the disease making it an attractive target for disease modification and neuroprotection. Thus, immunotherapies targeting aSyn are currently being investigated in pre-clinical and clinical trials. The focus of this review is to highlight the role of aSyn in neuroinflammation and discuss the current status of aSyn-directed immunotherapies in pre-clinical and clinical trials for PD.
Sheila M Fleming
Ashley Davis
Emily Simons
Neuropharmacology
. 2022 Jan 1;202:108870. doi: 10.1016/j.neuropharm.2021.108870. Epub 2021 Nov 3.
2022
English
The glycoprotein GPNMB attenuates astrocyte inflammatory responses through the CD44 receptor.
Astrocyte; CD44; GPNMB; Neuroinflammation; Parkinson's disease
BACKGROUND: Neuroinflammation is one of the hallmarks of neurodegenerative diseases, such as Parkinson's disease (PD). Activation of glial cells, including microglia and astrocytes, is a characteristic of the inflammatory response. Glycoprotein non-metastatic melanoma protein B (GPNMB) is a transmembrane glycoprotein that releases a soluble signaling peptide when cleaved by ADAM10 or other extracellular proteases. GPNMB has demonstrated a neuroprotective role in animal models of ALS and ischemia. However, the mechanism of this protection has not been well established. CD44 is a receptor expressed on astrocytes that can bind GPNMB, and CD44 activation has been demonstrated to reduce NFkappaB activation and subsequent inflammatory responses in macrophages. GPNMB signaling has not been investigated in models of PD or specifically in astrocytes. More recently, genetic studies have linked polymorphisms in GPNMB with risk for PD. Therefore, it is important to understand the role this signaling protein plays in PD. METHODS: We used data mining techniques to evaluate mRNA expression of GPNMB and its receptor CD44 in the substantia nigra of PD and control brains. Immunofluorescence and qPCR techniques were used to assess GPNMB and CD44 levels in mice treated with MPTP. In vitro experiments utilized the immortalized mouse astrocyte cell line IMA2.1 and purified primary mouse astrocytes. The effects of recombinant GPNMB on cytokine-induced astrocyte activation was determined by qPCR, immunofluorescence, and measurement of nitric oxide and reactive oxygen production. RESULTS: Increased GPNMB and CD44 expression was observed in the substantia nigra of human PD brains and in GFAP-positive astrocytes in an animal model of PD. GPNMB treatment attenuated cytokine-induced levels of inducible nitric oxide synthase, nitric oxide, reactive oxygen species, and the inflammatory cytokine IL-6 in an astrocyte cell line and primary mouse astrocytes. Using primary mouse astrocytes from CD44 knockout mice, we found that the anti-inflammatory effects of GPNMB are CD44-mediated. CONCLUSIONS: These results demonstrate that GPNMB may exert its neuroprotective effect through reducing astrocyte-mediated neuroinflammation in a CD44-dependent manner, providing novel mechanistic insight into the neuroprotective properties of GPNMB.
Neal Matthew L; Boyle Alexa M; Budge Kevin M; Safadi Fayez F; Richardson Jason R
Journal of neuroinflammation
2018
2018-03
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1186/s12974-018-1100-1" target="_blank" rel="noreferrer noopener">10.1186/s12974-018-1100-1</a>
The Microbiota-Gut-Brain Axis-Heart Shunt Part II: Prosaic Foods and the Brain-Heart Connection in Alzheimer Disease.
Alzheimer disease; brain; cerebrovascular; co-metabolism; French paradox; heart; microbiota-gut-brain axis; Parkinson's disease; polyphenol; prosaic foods; red wine; trimethylamine-N-oxide (TMANO/TMAO)
There is a strong cerebrovascular component to brain aging, Alzheimer disease, and vascular dementia. Foods, common drugs, and the polyphenolic compounds contained in wine modulate health both directly and through the gut microbiota. This observation and novel findings centered on nutrition, biochemistry, and metabolism, as well as the newer insights we gain into the microbiota-gut-brain axis, now lead us to propose a shunt to this classic triad, which involves the heart and cerebrovascular systems. The French paradox and prosaic foods, as they relate to the microbiota-gut-brain axis and neurodegenerative diseases, are discussed in this manuscript, which is the second part of a two-part series of concept papers addressing the notion that the microbiota and host liver metabolism all play roles in brain and heart health.
Obrenovich Mark; Tabrez Shams; Siddiqui Bushra; McCloskey Benjamin; Perry George
Microorganisms
2020
2020-03-31
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.3390/microorganisms8040493" target="_blank" rel="noreferrer noopener">10.3390/microorganisms8040493</a>
Time course and magnitude of alpha-synuclein inclusion formation and nigrostriatal degeneration in the rat model of synucleinopathy triggered by intrastriatal α-synuclein preformed fibrils
Alpha-Synuclein; PARKINSON'S disease; Preformed fibrils; Synucleinopathy
Animal models that accurately recapitulate the accumulation of alpha-synuclein (α-syn) inclusions, progressive neurodegeneration of the nigrostriatal system and motor deficits can be useful tools for Parkinson's disease (PD) research. The preformed fibril (PFF) synucleinopathy model in rodents generally displays these PD-relevant features, however, the magnitude and predictability of these events is far from established. We therefore sought to optimize the magnitude of α-syn accumulation and nigrostriatal degeneration, and to understand the time course of both. Rats were injected unilaterally with different quantities of α-syn PFFs (8 or 16 μg of total protein) into striatal sites selected to concentrate α-syn inclusion formation in the substantia nigra pars compacta (SNpc). Rats displayed an α-syn PFF quantity-dependent increase in the magnitude of ipsilateral SNpc inclusion formation at 2 months and bilateral loss of nigral dopamine neurons at 6 months. Unilateral 16 μg PFF injection also resulted in modest sensorimotor deficits in forelimb adjusting steps associated with degeneration at 6 months. Bilateral injection of 16 μg α-syn PFFs resulted in symmetric bilateral degeneration equivalent to the ipsilateral nigral degeneration observed following unilateral 16 μg PFF injection (~50% loss). Bilateral PFF injections additionally resulted in alterations in several gait analysis parameters. These α-syn PFF parameters can be applied to generate a reproducible synucleinopathy model in rats with which to study pathogenic mechanisms and vet potential disease-modifying therapies.
Patterson Joseph R; Duffy Megan F; Kemp Christopher J; Howe Jacob W; Collier Timothy J; Stoll Anna C; Miller Kathryn M; Patel Pooja; Levine Nathan; Moore Darren J; Luk Kelvin C; Fleming Sheila M; Kanaan Nicholas M; Paumier Katrina L; El-Agnaf Omar M A; Sortwell Caryl E
Neurobiology of Disease
2019
2019-10
<a href="http://doi.org/10.1016/j.nbd.2019.104525" target="_blank" rel="noreferrer noopener">10.1016/j.nbd.2019.104525</a>
Transgenic Overexpression of GPNMB Protects Against MPTP-Induced Neurodegeneration.
GPNMB; Microglia; MPTP; Neuroinflammation; Neuroprotective; Parkinson's disease
Parkinson's disease (PD) is a progressive neurodegenerative disease highlighted by a marked loss of dopaminergic cell loss and motor disturbances. Currently, there are no drugs that slow the progression of the disease. A myriad of factors have been implicated in the pathogenesis and progression of PD including neuroinflammation. Although anti-inflammatory agents are being evaluated as potential disease-modifying therapies for PD, none has proven effective to date, suggesting that new and novel targets are needed. Glycoprotein nonmetastatic melanoma protein B (GPNMB) is a transmembrane glycoprotein that has recently been shown to reduce inflammation in astrocytes and to be increased in post-mortem PD brain samples. Here we show that transgenic overexpression of GPNMB protects against dopaminergic neurodegeneration in a
Budge Kevin; Neal Matthew L; Richardson Jason R; Safadi Fayez F
Molecular neurobiology
2020
2020-05-20
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.1007/s12035-020-01921-6" target="_blank" rel="noreferrer noopener">10.1007/s12035-020-01921-6</a>