Calpain-Cleavage of α-Synuclein

Dufty, Brian M.; Warner, Lisa; Hou, Sheng T.; Jiang, Shuxian; Gómez-Isla, Teresa; Leenhouts, Kristen M.; Oxford, Julia Thom; Feany, Mel Β.; Masliah, Eliezer; Rohn, Troy T.

doi:10.2353/ajpath.2007.061232

Cited by 213 publications

(108 citation statements)

References 51 publications

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“…Accumulation of CT α-syn could result from elevated proteolytic cleavage by enzymes, such as calpain [26, 62], or from nonspecific breakdown due to detergents used in the SDS-PAGE. Since A30P+P mice displayed an increased amount of CT α-syn, co-migrating with calpain-cleaved recombinant α-syn, we hypothesized that an additional calpain treatment would accentuate its immunodominance.…”

Section: Resultsmentioning

confidence: 99%

“…Taken together, this strongly suggests accumulation of calpain 1-cleaved α-syn in A30P+P mice as opposed to breakdown artifacts in the SDS-PAGE. Indeed, owing to the presence of CT α-syn in LB [1, 26] and its capacity to aggravate aggregation pathology in vitro [46] and in vivo [91] it is widely believed that CT of α-syn plays a central role in α-syn aggregation pathology.…”

Section: Discussionmentioning

confidence: 99%

“…Calpain digestion of recombinant α-syn was performed as previously described [26]. Briefly, 15 μg of recombinant α-syn was incubated with calpain I (2 U) in buffer containing 40 mM HEPES and 1 mM calcium at 37 °C.…”

Section: Methodsmentioning

confidence: 99%

“…The accumulation of α-syn oligomers, rather than fibrils, has been proposed as key event for nigral DAergic cell vulnerability [17] and is possibly caused by either (1) its interaction with dopamine (DA) [10, 16, 73]; (2) single point mutations such as the A30P mutation [15], or (3) proteolytic cleavage leading to C-terminally truncation [26, 48, 62]. Several pan-neuronal α-syn transgenic animal models develop early symptoms that may precede nigral DAergic cell loss, including smell deficiency [29, 45, 70], and hyperactivity [43, 44, 81, 106].…”

Section: Introductionmentioning

confidence: 99%

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Environmental neurotoxic challenge of conditional alpha-synuclein transgenic mice predicts a dopaminergic olfactory-striatal interplay in early PD

et al. 2014

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The olfactory bulb (OB) is one of the first brain regions in Parkinson’s disease (PD) to contain alpha-synuclein (α-syn) inclusions, possibly associated with nonmotor symptoms. Mechanisms underlying olfactory synucleinopathy, its contribution to progressive aggregation pathology and nigrostriatal dopaminergic loss observed at later stages, remain unclear. A second hit, such as environmental toxins, is suggestive for α-syn aggregation in olfactory neurons, potentially triggering disease progression. To address the possible pathogenic role of olfactory α-syn accumulation in early PD, we exposed mice with site-specific and inducible overexpression of familial PD-linked mutant α-syn in OB neurons to a low dose of the herbicide paraquat. Here, we found that olfactory α-syn per se elicited structural and behavioral abnormalities, characteristic of an early time point in models with widespread α-syn expression, including hyperactivity and increased striatal dopaminergic marker. Suppression of α-syn reversed the dopaminergic phenotype. In contrast, paraquat treatment synergistically induced degeneration of olfactory dopaminergic cells and opposed the higher reactive phenotype. Neither neurodegeneration nor behavioral abnormalities were detected in paraquat-treated mice with suppressed α-syn expression. By increasing calpain activity, paraquat induced a pathological cascade leading to inhibition of autophagy clearance and accumulation of calpain-cleaved truncated and insoluble α-syn, recapitulating biochemical and structural changes in human PD. Thus our results underscore the primary role of proteolytic failure in aggregation pathology. In addition, we provide novel evidence that olfactory dopaminergic neurons display an increased vulnerability toward neurotoxins in dependence to presence of human α-syn, possibly mediating an olfactory-striatal dopaminergic network dysfunction in mouse models and early PD.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Environmental neurotoxic challenge of conditional alpha-synuclein transgenic mice predicts a dopaminergic olfactory-striatal interplay in early PD

et al. 2014

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“…The modifications done in C-terminal region may protect the various cleavage sites and also stabilize α-syn protein against proteolytically accessible conformations. As a result, the C-terminal truncation can generate production of toxic aggregates and hence promotes the neuro-degeneration process [43][44][45][60][61][62][63][64][65][66][67][68][69][70].…”

Section: Introductionmentioning

confidence: 99%

Effect of C-Terminal Truncations on the Aggregation Propensity of Α- Synuclein - A Potential of Mean Force Study

Sanjeev¹,

Mattaparthi²

2017

J Mol Imaging Dynam

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Abstractα-Synuclein is an intrinsically disordered protein which has a prominent role in Parkinson's disease (PD). Several familial variants of α-synuclein have been reported to associate with inherited PD. Several studies have highlighted the presence and association of the C-terminus of truncated forms of α-synuclein with Wild type α-synuclein (WT α-syn) at much higher level in patients with Lewy body diseases and they are found to decrease the reductive capabilities and potentially results in permanent oxidation of α-synuclein. To understand the impact of C-terminal truncations on the aggregation propensity of WT α-syn, the inter-molecular interactions between them are critical. Here we demonstrate the interactions between the WT α-syn and its three C-terminal truncations 95 (α-syn 95), 120 (α-syn 120) and 123 (α-syn 123), using Molecular Dynamics Simulations and Potential of Mean Force study (PMF). From the PMF study, we observed C-terminal truncation 120 (α-syn 120) to bind strongly to WT α-syn than the other truncated forms of α-synuclein. We also noticed number of hydrogen bonds to be larger, high geometrical shape complementarity score, larger number of interface residues and interface area for the hetero-dimer (WT α-syn-α-syn 120) than other hetero-dimers (WT α-syn -α-syn 95/123). We therefore can infer that among α-syn 95, α-syn 120 and α-syn 123, α-syn 120 to show more association with WT α-syn. This is because in α-syn 120, more amino acids have been removed in comparison to α-syn 123. In contrast, α-Syn 95 shows less interaction with WT α-syn because of the absence of the entire C-terminal region. Our findings suggest that more the truncation on the Cterminal region of α-synuclein more will the effect on its aggregation.

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Head injury, alpha‐synuclein Rep1, and Parkinson's disease

Goldman

Kamel

Ross

et al. 2012

Annals of Neurology

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Objective To test the hypothesis that variability in SNCA Rep1, a polymorphic dinucleotide microsatellite in the promoter region of the gene encoding α-synuclein, modifies the association between head injury and Parkinson’s disease (PD) risk. Methods Participants in Farming and Movement Evaluation (FAME) and Study of Environmental Association and Risk of Parkinsonism using Case-Control Historical Interviews (SEARCH), two independent case-control studies, were genotyped for Rep1 and interviewed regarding head injuries with loss of consciousness or concussion prior to PD diagnosis. Logistic regression modeling adjusted for potential confounding variables and tested interaction between Rep1 genotype and head injury. Results Consistent with prior reports, relative to medium-length Rep1, short Rep1 genotype was associated with reduced PD risk (pooled odds ratio (OR) 0.7, 95% confidence interval (CI) 0.5-0.9), and long Rep1 with increased risk (pooled OR 1.4, 95%CI 0.95-2.2). Overall, head injury was not significantly associated with PD (pooled OR 1.3, 95%CI 0.9-1.8). However, head injury was strongly associated with PD in those with long Rep1 (FAME OR 5.4, 95%CI 1.5-19; SEARCH OR 2.3, 95%CI 0.6-9.2; pooled OR 3.5, 95%CI 1.4-9.2, p-interaction 0.02). Individuals with both head injury and long Rep1 were diagnosed 4.9 years earlier than those with neither risk factor (p = 0.03). Interpretation While head injury alone was not associated with PD risk, our data suggest head injury may initiate and/or accelerate neurodegeneration when levels of synuclein are high, as in those with Rep1 expansion. Given the high population frequency of head injury, independent verification of these results is essential.

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Calpain-Cleavage of α-Synuclein

Cited by 213 publications

References 51 publications

Environmental neurotoxic challenge of conditional alpha-synuclein transgenic mice predicts a dopaminergic olfactory-striatal interplay in early PD

Environmental neurotoxic challenge of conditional alpha-synuclein transgenic mice predicts a dopaminergic olfactory-striatal interplay in early PD

Effect of C-Terminal Truncations on the Aggregation Propensity of Α- Synuclein - A Potential of Mean Force Study

Head injury, alpha‐synuclein Rep1, and Parkinson's disease

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