Dopaminergic Loss and Inclusion Body Formation in α-Synuclein Mice: Implications for Neurodegenerative Disorders

Masliah, Eliezer; Rockenstein, Edward; Veinbergs, Isaac; Mallory, Margaret; Hashimoto, Makoto; Takeda, Ayako; Sagara, Yutaka; Sisk, Abbyann; Mucke, Lennart

doi:10.1126/science.287.5456.1265

Cited by 1,668 publications

(1,383 citation statements)

References 25 publications

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“…It is highly expressed in presynaptic neurons and although its normal function is not known, it is speculated to be involved with transport. Overexpression of a-synuclein in a transgenic organism resulted in a parkinsonian-like phenotype (Masliah et al 2000) as well as mutated forms found in early onset Parkinson's disease in humans (Kruger et al 1998;Polymeropoulos et al 1997), suggesting that abnormal expression/function contributes to the neurodegenerativeprocess. Mutated forms of a-synuclein were found to affect membrane binding and association to brain vesicles (Jensen et al 1998).…”

Section: Discussionmentioning

confidence: 99%

“…In vitro, the phosphorylation of serine-129 has been shown to promote fibril formation, a particular form of aggregation, and often thought to be associated with disease . All mouse models of overexpressed a-synuclein (Masliah et al 2000;van der Putten et al 2000) and in vitro studies with wild-type and early-onset Parkinson's disease mutant a-synuclein produce non-fibrillar oligomers (Conway et al 2000). However, the Drosophila model of a-synuclein did produce fibrils (Feany and Bender 2000).…”

Section: Discussionmentioning

confidence: 99%

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Mice expressing the α_1B‐adrenergic receptor induces a synucleinopathy with excessive tyrosine nitration but decreased phosphorylation

Papay

Zuscik

Ross

et al. 2002

Journal of Neurochemistry

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We had previously reported that systemic overexpression of the a 1B -adrenergic receptor (AR) in a transgenic mouse induced a neurodegenerative disease that resembled the parkinsonian-like syndrome called multiple system atrophy (MSA). We now report that our mouse model has cytoplasmic inclusion bodies that colocalize with oligodendrocytes and neurons, are positive for a-synuclein and ubiquitin, and therefore may be classified as a synucleinopathy. a-Synuclein monomers as well as multimers were present in brain extracts from both normal and transgenic mice. However, similar to human MSA and other synucleinopathies, transgenic mice showed an increase in abnormal aggregated forms of a-synuclein, which also increased its nitrated content with age.However, the same extracts displayed decreased phosphorylation of a-synuclein. Other traits particular to MSA such as Purkinje cell loss in the cerebellum and degeneration of the intermediolateral cell columns of the spinal cord also exist in our mouse model but differences still exist between them. Interestingly, long-term therapy with the a 1 -AR antagonist, terazosin, resulted in protection against the symptomatic as well as the neurodegeneration and a-synuclein inclusion body formation, suggesting that signaling of the a 1B -AR is the cause of the pathology. We conclude that overexpression of the a 1B -AR can cause a synucleinopathy similar to other parkinsonian syndromes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Mice expressing the α_1B‐adrenergic receptor induces a synucleinopathy with excessive tyrosine nitration but decreased phosphorylation

Papay

Zuscik

Ross

et al. 2002

Journal of Neurochemistry

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“…1) were developed in the laboratory of Eliezer Masliah at UCSD [21] and were designated "line 61" to differentiate them from a previously published line driven by the PDGF promoter (line D: [22]). The 2 lines markedly differ in the pattern of alpha-synuclein over-expression and level [21,23].…”

Section: General Descriptionmentioning

confidence: 99%

A Progressive Mouse Model of Parkinson's Disease: The Thy1-aSyn (“Line 61”) Mice

et al. 2012

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Identification of mutations that cause rare familial forms of Parkinson's disease (PD) and subsequent studies of genetic risk factors for sporadic PD have led to an improved understanding of the pathological mechanisms that may cause nonfamilial PD. In particular, genetic and pathological studies strongly suggest that alpha-synuclein, albeit very rarely mutated in PD patients, plays a critical role in the vast majority of individuals with the sporadic form of the disease. We have extensively characterized a mouse model over-expressing full-length, human, wild-type alpha-synuclein under the Thy-1 promoter. We have also shown that this model reproduces many features of sporadic PD, including progressive changes in dopamine release and striatal content, alphasynuclein pathology, deficits in motor and nonmotor functions that are affected in pre-manifest and manifest phases of PD, inflammation, and biochemical and molecular changes similar to those observed in PD. Preclinical studies have already demonstrated improvement with promising new drugs in this model, which provides an opportunity to test novel neuroprotective strategies during different phases of the disorder using endpoint measures with high power to detect drug effects.

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“…This model was selected because mice from this line develop ha-synuclein immunoreactive inclusions distributed through the neocortex and hippocampus similar to what has been described in DLB. [46][47][48] A total of 48 ha-synuclein tg mice from line D (12 months old) were injected with 3 ml of the lentiviral preparations (1.5 Â 10 7 TU) into the temporal cortex and hippocampus. Briefly, as previously described, 45 mice were placed under anesthesia on a Koft stereotaxic apparatus and coordinates (AP -1.5 mm, lateral 1 mm, depth 2 mm) were determined as per the Franklin and Paxinos Atlas.…”

Section: Transgenic Mouse Lines and Intracerebral Injections Of Lentimentioning

confidence: 99%

An antiaggregation gene therapy strategy for Lewy body disease utilizing β-synuclein lentivirus in a transgenic model

et al. 2004

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Current experimental gene therapy approaches for Parkinson's disease (PD) and dementia with Lewy bodies (DLB) include the use of viral vectors expressing antiapoptosis genes, neurotrophic factors and dopaminergic system enzymes. However, since increasing evidence favors a role for a-synuclein accumulation in the pathogenesis of these disorders, an alternative therapy might require the transfer of genes that might block a-synuclein accumulation. b-Synuclein, the nonamyloidogenic homologue of a-synuclein, has recently been identified as a potential candidate. Thus, in vivo transfer of genes encoding b-synuclein might provide a novel approach to the development of experimental treatments for PD and DLB. To assess this possibility and to better understand the mechanisms involved, a lentiviral vector expressing human (h) b-synuclein (lenti-b-synuclein) was tested in a transgenic (tg) mouse model of ha-synuclein aggregation. This study showed that unilateral intracerebral injection of lenti-b-synuclein reduced the formation of hasynuclein inclusions and the accumulation of ha-synuclein in synapses and ameliorated the neurodegenerative alterations in the tg mice. Both in vivo and in vitro coimmunoprecipitation and immunoblot experiments show that the mechanisms of b-synuclein neuroprotection involve binding of this molecule to ha-synuclein and Akt, resulting in the decreased aggregation and accumulation of ha-synuclein in the synaptic membrane. Together, these data further support a role for b-synuclein in regulating the conformational state of a-synuclein and suggest that this gene transfer approach might have potential for the development of alternative therapies for PD and DLB.

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Dopaminergic Loss and Inclusion Body Formation in α-Synuclein Mice: Implications for Neurodegenerative Disorders

Cited by 1,668 publications

References 25 publications

Mice expressing the α_1B‐adrenergic receptor induces a synucleinopathy with excessive tyrosine nitration but decreased phosphorylation

Mice expressing the α_1B‐adrenergic receptor induces a synucleinopathy with excessive tyrosine nitration but decreased phosphorylation

A Progressive Mouse Model of Parkinson's Disease: The Thy1-aSyn (“Line 61”) Mice

An antiaggregation gene therapy strategy for Lewy body disease utilizing β-synuclein lentivirus in a transgenic model

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Dopaminergic Loss and Inclusion Body Formation in α-Synuclein Mice: Implications for Neurodegenerative Disorders

Cited by 1,668 publications

References 25 publications

Mice expressing the α1B‐adrenergic receptor induces a synucleinopathy with excessive tyrosine nitration but decreased phosphorylation

Mice expressing the α1B‐adrenergic receptor induces a synucleinopathy with excessive tyrosine nitration but decreased phosphorylation

A Progressive Mouse Model of Parkinson's Disease: The Thy1-aSyn (“Line 61”) Mice

An antiaggregation gene therapy strategy for Lewy body disease utilizing β-synuclein lentivirus in a transgenic model

Contact Info

Product

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Mice expressing the α_1B‐adrenergic receptor induces a synucleinopathy with excessive tyrosine nitration but decreased phosphorylation

Mice expressing the α_1B‐adrenergic receptor induces a synucleinopathy with excessive tyrosine nitration but decreased phosphorylation