AlaSOPro mutation in the gene encoding α-synuclein in Parkinson's disease

Krüger, Rejko; Kühn, Wilfried; Müller, Thomas; Woitalla, Dirk; Graeber, Manuel B.; Kösel, S.; Przuntek, H.; Epplen, Jörg T.; Schöls, Ludger; Rieß, Olaf

doi:10.1038/ng0298-106

Cited by 3,688 publications

(2,441 citation statements)

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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%

“…Our model is particularly well-suited since it is not created through drug-induced infusions often used in mouse models of Parkinson's disease. Rather, it represents a naturally progressing disease derived from a genetic determinant that resembles the symptoms of some early onset Parkinson's patients with mutations in the a-synuclein gene (Polymeropoulos et al 1997;Kruger et al 1998). Since we measured a partial rescue of the symptoms of neurodegeneration in the transgenic mouse with shortterm terazosin treatment (Zuscik et al 2000), we hypothesized that long-term administration of the same drug would be protective of the disease.…”

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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“…Mis‐sense mutations13, 36, 37, 38, 39, 40 and duplications or triplications of the SNCA gene, which encodes αS, lead to autosomal dominant early onset PD 41, 42. It has previously been shown that the formation of αS oligomers in vitro is concentration dependent,12 and ADPAINT now enables us to determine whether this dependence is reflected in cellular models that overexpress αS.…”

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confidence: 99%

Nanoscopic Characterisation of Individual Endogenous Protein Aggregates in Human Neuronal Cells

et al. 2018

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The aberrant misfolding and subsequent conversion of monomeric protein into amyloid aggregates characterises many neurodegenerative disorders, including Parkinson's and Alzheimer's diseases. These aggregates are highly heterogeneous in structure, generally of low abundance and typically smaller than the diffraction limit of light (≈250 nm). To overcome the challenges these characteristics pose to the study of endogenous aggregates formed in cells, we have developed a method to characterise them at the nanometre scale without the need for a conjugated fluorophore. Using a combination of DNA PAINT and an amyloid‐specific aptamer, we demonstrate that this technique is able to detect and super‐resolve a range of aggregated species, including those formed by α‐synuclein and amyloid‐β. Additionally, this method enables endogenous protein aggregates within cells to be characterised. We found that neuronal cells derived from patients with Parkinson's disease contain a larger number of protein aggregates than those from healthy controls.

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“…To address the potential role for α-synuclein in brain 20:4n-6 uptake and metabolism, we used steady-state kinetic modeling of [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]20:4n-6 metabolism in vivo coupled with studies using enzyme assays and mRNA expression of key fatty acid metabolic enzymes. These data show, for the first time, a mechanistic explanation for the impact of α-synuclein deficiency on brain lipid metabolism.…”

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confidence: 99%

Acyl-CoA Synthetase Activity Links Wild-Type but Not Mutant α-Synuclein to Brain Arachidonate Metabolism

et al. 2006

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Because α-synuclein (Snca) has a role in brain lipid metabolism, we determined the impact that the loss of α-synuclein had on brain arachidonic acid (20:4n-6) metabolism in vivo using Snca -/-mice. We measured [1-14 C]20:4n-6 incorporation and turnover kinetics in brain phospholipids using an established steady-state kinetic model. Liver was used as a negative control and no changes were observed between groups. In Snca -/-brains, there was a marked reduction in 20:4n-6-CoA mass and in microsomal acyl-CoA synthetases (Acsl) activity toward 20:4n-6. Microsomal Acsl activity was completely restored after the addition of exogenous wt mouse or human α-synuclein, but not by A30P, E46K, and A53T forms of α-synuclein. Acsl and acyl-CoA hydrolase expression was not different between groups. The incorporation and turnover of 20:4n-6 into brain phospholipid pools was markedly reduced. The dilution coefficient lambda, which indicates 20:4n-6 recycling between the acyl-CoA pool and brain phospholipids, was increased 3.3-fold, indicating more 20:4n-6 was entering the 20:4n-6-CoA pool from the plasma relative to that being recycled from the phospholipids. This is consistent with the reduction in Acsl activity observed in the Snca -/-mice. Using titration microcalorimetry, we determined that α-synuclein bound free 20:4n-6 (K d of 3.7 μM), but did not bind 20:4n-6-CoA. These data suggest α-synuclein is involved in substrate presentation to Acsl rather than product removal. In summary, our data demonstrate that α-synuclein has a major role in brain 20:4n-6 metabolism through its modulation of endoplasmic reticulum localized acyl-CoA synthetase activity, although mutants forms of α-synuclein fail to restore this activity. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript α-Synuclein is a 140 amino acid soluble protein that is highly expressed in the central nervous system (1,2) and is abundant in presynaptic terminals of neurons (1,(3)(4)(5). α-Synuclein is also found in other regions of neurons, in astrocytes, and in oligodendroglia (6-11). Overexpression of and mutations in α-synuclein are associated with early onset Parkinson's disease (12)(13)(14)(15) and other neurodegenerative diseases (16)(17)(18)(19)(20). Despite this association with neurodegenerative diseases, the physiological function of this protein remains unclear.Several lines of evidence suggest that α-synuclein can influence brain lipid metabolism. It has structural similarities to class A2 apolipoproteins (21,22) and to fatty acid binding proteins (23), suggesting that α-synuclein may alter intracellular lipid trafficking, the regulation of lipid metabolism, and may act to stabilize lipid membranes. α-Synuclein binds to small phospholipid vesicles (22,24,25) and to brain vesicles (26). Consistent with this binding, the lack of α-synuclein decreases the resting/reserve pool of synaptic vesicles (27,28). Although the direct binding of fatty acids is controversial (23,29), recent studies indicate a strong potential for an important ...

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AlaSOPro mutation in the gene encoding α-synuclein in Parkinson's disease

Cited by 3,688 publications

References 9 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

Nanoscopic Characterisation of Individual Endogenous Protein Aggregates in Human Neuronal Cells

Acyl-CoA Synthetase Activity Links Wild-Type but Not Mutant α-Synuclein to Brain Arachidonate Metabolism

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AlaSOPro mutation in the gene encoding α-synuclein in Parkinson's disease

Cited by 3,688 publications

References 9 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

Nanoscopic Characterisation of Individual Endogenous Protein Aggregates in Human Neuronal Cells

Acyl-CoA Synthetase Activity Links Wild-Type but Not Mutant α-Synuclein to Brain Arachidonate Metabolism

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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