Interaction between subclinical doses of the Parkinson’s disease associated gene, α -synuclein , and the pesticide, rotenone, precipitates motor dysfunction and nigrostriatal neurodegeneration in rats

Naughton, Carol; O’Toole, Daniel; Kirik, Deniz; Dowd, Eilís

doi:10.1016/j.bbr.2016.08.056

Cited by 23 publications

(9 citation statements)

References 35 publications

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“…Furthermore, a study carried out by a previous member of our research group found that the sequential intra-nigral administration of AAV-α-synuclein and the pesticide rotenone significantly exacerbated nigrostriatal degeneration and induced a progressive decline in motor function [ 30 ]. Sequential administration of subclinical doses of intra-nigral AAV-α-synuclein and intra-striatal rotenone similarly precipitated motor impairment and degeneration of nigral cell bodies [ 31 ]. Undoubtedly, there is enormous potential in using a dual approach to modelling Parkinson’s disease pathology.…”

Section: Discussionmentioning

confidence: 99%

The Small Molecule Alpha-Synuclein Aggregator, FN075, Enhances Alpha-Synuclein Pathology in Subclinical AAV Rat Models

et al. 2021

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Animal models of Parkinson’s disease, in which the human α-synuclein transgene is overexpressed in the nigrostriatal pathway using viral vectors, are widely considered to be the most relevant models of the human condition. However, although highly valid, these models have major limitations related to reliability and variability, with many animals exhibiting pronounced α-synuclein expression failing to demonstrate nigrostriatal neurodegeneration or motor dysfunction. Therefore, the aim of this study was to determine if sequential intra-nigral administration of AAV-α-synuclein followed by the small α-synuclein aggregating molecule, FN075, would enhance or precipitate the associated α-synucleinopathy, nigrostriatal pathology and motor dysfunction in subclinical models. Rats were given unilateral intra-nigral injections of AAV-α-synuclein (either wild-type or A53T mutant) followed four weeks later by a unilateral intra-nigral injection of FN075, after which they underwent behavioral testing for lateralized motor functionality until they were sacrificed for immunohistological assessment at 20 weeks after AAV administration. In line with expectations, both of the AAV vectors induced widespread overexpression of human α-synuclein in the substantia nigra and striatum. Sequential administration of FN075 significantly enhanced the α-synuclein pathology with increased density and accumulation of the pathological form of the protein phosphorylated at serine 129 (pS129-α-synuclein). However, despite this enhanced α-synuclein pathology, FN075 did not precipitate nigrostriatal degeneration or motor dysfunction in these subclinical AAV models. In conclusion, FN075 holds significant promise as an approach to enhancing the α-synuclein pathology in viral overexpression models, but further studies are required to determine if alternative administration regimes for this molecule could improve the reliability and variability in these models.

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Section: Discussionmentioning

confidence: 99%

The Small Molecule Alpha-Synuclein Aggregator, FN075, Enhances Alpha-Synuclein Pathology in Subclinical AAV Rat Models

et al. 2021

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“…Recently, new rodent models has emerged using αsyn overpexression in combination with other risk factors contributing to the disease. A dual exposure of αsyn, and the pesticide, rotenone, in rodent has been reported to to precipitate motor dysfunction and nigrostriatal neurodegeneration [34]. Thus, using genetic component with environmental risk factors or other disease-causing factors may be another approach to provide relevant preclinical models that replicate motor dysfunctions.…”

Section: Discussionmentioning

confidence: 99%

Neonatal AAV delivery of alpha-synuclein induces pathology in the adult mouse brain

Delenclos

Faroqi

Yue

et al. 2017

acta neuropathol commun

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Abnormal accumulation of alpha-synuclein (αsyn) is a pathological hallmark of Lewy body related disorders such as Parkinson’s disease and Dementia with Lewy body disease. During the past two decades, a myriad of animal models have been developed to mimic pathological features of synucleinopathies by over-expressing human αsyn. Although different strategies have been used, most models have little or no reliable and predictive phenotype. Novel animal models are a valuable tool for understanding neuronal pathology and to facilitate development of new therapeutics for these diseases. Here, we report the development and characterization of a novel model in which mice rapidly express wild-type αsyn via somatic brain transgenesis mediated by adeno-associated virus (AAV). At 1, 3, and 6 months of age following intracerebroventricular (ICV) injection, mice were subjected to a battery of behavioral tests followed by pathological analyses of the brains. Remarkably, significant levels of αsyn expression are detected throughout the brain as early as 1 month old, including olfactory bulb, hippocampus, thalamic regions and midbrain. Immunostaining with a phospho-αsyn (pS129) specific antibody reveals abundant pS129 expression in specific regions. Also, pathologic αsyn is detected using the disease specific antibody 5G4. However, this model did not recapitulate behavioral phenotypes characteristic of rodent models of synucleinopathies. In fact no deficits in motor function or cognition were observed at 3 or 6 months of age. Taken together, these findings show that transduction of neonatal mouse with AAV-αsyn can successfully lead to rapid, whole brain transduction of wild-type human αsyn, but increased levels of wildtype αsyn do not induce behavior changes at an early time point (6 months), despite pathological changes in several neurons populations as early as 1 month.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-017-0455-3) contains supplementary material, which is available to authorized users.

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“…Parkinson’s disease-related neurodegeneration is likely to occur several decades before the onset of the motor symptoms [20]. Associated with different potentially pathogenic risk factors (toxins, drugs, pesticides, brain microtrauma, focal cerebrovascular damage, genomic defects), PD neuropathology is characterized by a selective loss of dopaminergic neurons in the substantia nigra pars compacta and Lewy body deposition, with widespread involvement of other CNS structures and peripheral tissues [21,22,23]. Parkinson’s disease is a form of multisystemic α-synucleinopathy with Lewy bodies deposited in the midbrain.…”

Section: Pathogenic Mechanismsmentioning

confidence: 99%

Parkinson’s Disease: From Pathogenesis to Pharmacogenomics

Cacabelos

2017

IJMS

451

300

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Parkinson’s disease (PD) is the second most important age-related neurodegenerative disorder in developed societies, after Alzheimer’s disease, with a prevalence ranging from 41 per 100,000 in the fourth decade of life to over 1900 per 100,000 in people over 80 years of age. As a movement disorder, the PD phenotype is characterized by rigidity, resting tremor, and bradykinesia. Parkinson’s disease -related neurodegeneration is likely to occur several decades before the onset of the motor symptoms. Potential risk factors include environmental toxins, drugs, pesticides, brain microtrauma, focal cerebrovascular damage, and genomic defects. Parkinson’s disease neuropathology is characterized by a selective loss of dopaminergic neurons in the substantia nigra pars compacta, with widespread involvement of other central nervous system (CNS) structures and peripheral tissues. Pathogenic mechanisms associated with genomic, epigenetic and environmental factors lead to conformational changes and deposits of key proteins due to abnormalities in the ubiquitin–proteasome system together with dysregulation of mitochondrial function and oxidative stress. Conventional pharmacological treatments for PD are dopamine precursors (levodopa, l-DOPA, l-3,4 dihidroxifenilalanina), and other symptomatic treatments including dopamine agonists (amantadine, apomorphine, bromocriptine, cabergoline, lisuride, pergolide, pramipexole, ropinirole, rotigotine), monoamine oxidase (MAO) inhibitors (selegiline, rasagiline), and catechol-O-methyltransferase (COMT) inhibitors (entacapone, tolcapone). The chronic administration of antiparkinsonian drugs currently induces the “wearing-off phenomenon”, with additional psychomotor and autonomic complications. In order to minimize these clinical complications, novel compounds have been developed. Novel drugs and bioproducts for the treatment of PD should address dopaminergic neuroprotection to reduce premature neurodegeneration in addition to enhancing dopaminergic neurotransmission. Since biochemical changes and therapeutic outcomes are highly dependent upon the genomic profiles of PD patients, personalized treatments should rely on pharmacogenetic procedures to optimize therapeutics.

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Interaction between subclinical doses of the Parkinson’s disease associated gene, α -synuclein , and the pesticide, rotenone, precipitates motor dysfunction and nigrostriatal neurodegeneration in rats

Cited by 23 publications

References 35 publications

The Small Molecule Alpha-Synuclein Aggregator, FN075, Enhances Alpha-Synuclein Pathology in Subclinical AAV Rat Models

The Small Molecule Alpha-Synuclein Aggregator, FN075, Enhances Alpha-Synuclein Pathology in Subclinical AAV Rat Models

Neonatal AAV delivery of alpha-synuclein induces pathology in the adult mouse brain

Parkinson’s Disease: From Pathogenesis to Pharmacogenomics

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