Modeling Parkinson’s Disease Neuropathology and Symptoms by Intranigral Inoculation of Preformed Human α-Synuclein Oligomers

Boi, Laura; Pisanu, Augusta; Palmas, Maria Francesca; Fusco, Giuliana; Carboni, Ezio; Casu, Maria Antonietta; Satta, Valentina; Scherma, María; Janda, Elżbieta; Mocci, Ignazia; Mulas, Giovanna; Ena, Anna; Spiga, Saturnino; Fadda, Paola; Simone, Alfonso De; Carta, Anna R.

doi:10.3390/ijms21228535

Cited by 26 publications

(40 citation statements)

References 83 publications

(147 reference statements)

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“…The use of oligomers or PFFs, either injected into the brain [71,140,141], or into the gut [76,142] is a second tool that has recently gained traction and is increasing our understanding of the nature of a-syn spread within the brain. PFFs cause robust DA cell death and show extensive spread of a-syn pathology across brain regions [100,143,144]. Ser-129 phosphorylation of endogenous a-syn in response to extracellular a-syn fibrils exerts profound effects on the ability of a-syn to form toxic aggregates [143], and may be of particular relevance to the spread of a-syn pathology across brain regions.…”

Section: Additional Tools To Model A-syn Pathology Pd In Rodentsmentioning

confidence: 99%

Adeno-Associated Virus Expression of α-Synuclein as a Tool to Model Parkinson’s Disease: Current Understanding and Knowledge Gaps

Huntington¹,

Srinivasan²

2021

Aging and disease

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Parkinson's disease (PD) is the second most common neurodegenerative disorder in the aging population and is characterized by a constellation of motor and non-motor symptoms. The abnormal aggregation and spread of alpha-synuclein (α-syn) is thought to underlie the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc), leading to the development of PD. It is in this context that the use of adenoassociated viruses (AAVs) to express a-syn in the rodent midbrain has become a popular tool to model SNc DA neuron loss during PD. In this review, we summarize results from two decades of experiments using AAVmediated a-syn expression in rodents to model PD. Specifically, we outline aspects of AAV vectors that are particularly relevant to modeling a-syn dysfunction in rodent models of PD such as changes in striatal neurochemistry, a-syn biochemistry, and PD-related behaviors resulting from AAV-mediated a-syn expression in the midbrain. Finally, we discuss the emerging role of astrocytes in propagating a-syn pathology, and point to future directions for employing AAVs as a tool to better understand how astrocytes contribute to a-syn pathology during the development of PD. We envision that lessons learned from two decades of utilizing AAVs to express a-syn in the rodent brain will enable us to develop an optimized set of parameters for gaining a better understanding of how a-syn leads to the development of PD.

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Section: Additional Tools To Model A-syn Pathology Pd In Rodentsmentioning

confidence: 99%

Adeno-Associated Virus Expression of α-Synuclein as a Tool to Model Parkinson’s Disease: Current Understanding and Knowledge Gaps

Huntington¹,

Srinivasan²

2021

Aging and disease

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“…The novel toxins human α-synuclein oligomers (H-αSynO) and recombinant α-synuclein fibrils can induce PD memory deficits by depleting early mitochondria in SN neurons, which damages nigrostriatal DAergic neurons and inhibits cortical and amygdala function ( Boi et al, 2020 ; Stoyka et al, 2020 ). These toxins can also induce p-α-Syn deposition in the SN neurons and microglia and spread to the striatum, which is a similar pathology to that of PD-MCI and PDD ( Boi et al, 2020 ).…”

Section: Neurotoxin-induced Experimental Models Of Cognitive Impairmentmentioning

confidence: 99%

Experimental Models of Cognitive Impairment for Use in Parkinson’s Disease Research: The Distance Between Reality and Ideal

Fan

Han

Zhao

et al. 2021

Front. Aging Neurosci.

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Parkinson’s disease (PD) is the second most common neurodegenerative disease. Cognitive impairment is one of the key non-motor symptoms of PD, affecting both mortality and quality of life. However, there are few experimental studies on the pathology and treatments of PD with mild cognitive impairment (PD-MCI) and PD dementia (PDD) due to the lack of representative models. To identify new strategies for developing representative models, we systematically summarized previous studies on PD-MCI and PDD and compared differences between existing models and diseases. Our initial search identified 5432 articles, of which 738 were duplicates. A total of 227 articles met our inclusion criteria and were included in the analysis. Models fell into three categories based on model design: neurotoxin-induced, transgenic, and combined. Although the neurotoxin-induced experimental model was the most common type that was used during every time period, transgenic and combined experimental models have gained significant recent attention. Unfortunately, there remains a big gap between ideal and actual experimental models. While each model has its own disadvantages, there have been tremendous advances in the development of PD models of cognitive impairment, and almost every model can verify a hypothesis about PD-MCI or PDD. Finally, our proposed strategies for developing novel models are as follows: a set of plans that integrate symptoms, biochemistry, neuroimaging, and other objective indicators to judge and identify that the novel model plays a key role in new strategies for developing representative models; novel models should simulate different clinical features of PD-MCI or PDD; inducible α-Syn overexpression and SH-SY5Y-A53T cellular models are good candidate models of PD-MCI or PDD.

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“…Which form of α-Syn is most toxic among intermediates of the aggregation process is still highly debated. However, several studies have shown that the interaction of α-Syn with TLRs is conformation-dependent, and short soluble aggregates such as oligomers display a greater inflammatory and neurotoxic potential than the native monomeric protein ( Zhang et al, 2005 ; Klegeris et al, 2008 ; Lee E. J. et al, 2010 ; Rojanathammanee et al, 2011 ; Fellner et al, 2013 ; Kim et al, 2013 ; Daniele et al, 2015 ; Boi et al, 2020 ).…”

Section: Neuroinflammation In Neurological Disordersmentioning

confidence: 99%

Repurposing Immunomodulatory Imide Drugs (IMiDs) in Neuropsychiatric and Neurodegenerative Disorders

et al. 2021

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Neuroinflammation represents a common trait in the pathology and progression of the major psychiatric and neurodegenerative disorders. Neuropsychiatric disorders have emerged as a global crisis, affecting 1 in 4 people, while neurological disorders are the second leading cause of death in the elderly population worldwide (WHO, 2001; GBD 2016 Neurology Collaborators, 2019). However, there remains an immense deficit in availability of effective drug treatments for most neurological disorders. In fact, for disorders such as depression, placebos and behavioral therapies have equal effectiveness as antidepressants. For neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease, drugs that can prevent, slow, or cure the disease have yet to be found. Several non-traditional avenues of drug target identification have emerged with ongoing neurological disease research to meet the need for novel and efficacious treatments. Of these novel avenues is that of neuroinflammation, which has been found to be involved in the progression and pathology of many of the leading neurological disorders. Neuroinflammation is characterized by glial inflammatory factors in certain stages of neurological disorders. Although the meta-analyses have provided evidence of genetic/proteomic upregulation of inflammatory factors in certain stages of neurological disorders. Although the mechanisms underpinning the connections between neuroinflammation and neurological disorders are unclear, and meta-analysis results have shown high sensitivity to factors such as disorder severity and sample type, there is significant evidence of neuroinflammation associations across neurological disorders. In this review, we summarize the role of neuroinflammation in psychiatric disorders such as major depressive disorder, generalized anxiety disorder, post-traumatic stress disorder, and bipolar disorder, as well as in neurodegenerative disorders, such as Parkinson’s disease and Alzheimer’s disease, and introduce current research on the potential of immunomodulatory imide drugs (IMiDs) as a new treatment strategy for these disorders.

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Modeling Parkinson’s Disease Neuropathology and Symptoms by Intranigral Inoculation of Preformed Human α-Synuclein Oligomers

Cited by 26 publications

References 83 publications

Adeno-Associated Virus Expression of α-Synuclein as a Tool to Model Parkinson’s Disease: Current Understanding and Knowledge Gaps

Adeno-Associated Virus Expression of α-Synuclein as a Tool to Model Parkinson’s Disease: Current Understanding and Knowledge Gaps

Experimental Models of Cognitive Impairment for Use in Parkinson’s Disease Research: The Distance Between Reality and Ideal

Repurposing Immunomodulatory Imide Drugs (IMiDs) in Neuropsychiatric and Neurodegenerative Disorders

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