The solubility of α‐synuclein in multiple system atrophy differs from that of dementia with Lewy bodies and Parkinson's disease

Campbell, Bruce C.V.; McLean, Catriona; Culvenor, Janetta G.; Gai, Wei; Blumbergs, Peter; Jäkälä, Pekka; Beyreuther, Konrad; Masters, Colin L.; Li, Qiao‐Xin

doi:10.1046/j.1471-4159.2001.00021.x

Cited by 206 publications

(127 citation statements)

References 36 publications

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“…As the concentration of monomeric α-syn increases, such that the molar ratio of monomeric α-syn:Hsp27 exceeds 1:1, aggregation occurs. This finding is significant given the association of early onset PD with duplication or triplication of the SNCA gene (56)(57)(58)(59)(60). In these cases, increases in the concentration of α-syn may allow aggregation-prone forms of α-syn to escape the protective capacity of the sHsps.…”

Section: Discussionmentioning

confidence: 99%

The small heat shock protein Hsp27 binds α-synuclein fibrils, preventing elongation and cytotoxicity

Cox

Whiten

Brown

et al. 2018

Journal of Biological Chemistry

101

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Section: Discussionmentioning

confidence: 99%

The small heat shock protein Hsp27 binds α-synuclein fibrils, preventing elongation and cytotoxicity

Cox

Whiten

Brown

et al. 2018

Journal of Biological Chemistry

101

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“…More importantly, C-terminal truncation elicits the production of toxic α-syn aggregates and promotes neurodegeneration (10-14, 34, 38-47). Some studies have shown that C-terminally truncated α-syn is found in GCIs in MSA (48,49) as well as in Lewy bodies of PD and DLB patient brains (11,12,39,50,51). Several proteases such as calpain, matrix metalloproteases (MMPs), cathepsin D, and plasmin have been implicated in α-syn truncation, subsequently resulting in increased levels of protein aggregates; however, none has been established as a major producer of C-terminally truncated α-syn in vivo, especially in response to inflammation (12,39,42,(52)(53)(54)(55).…”

Section: Discussionmentioning

confidence: 99%

Reducing C-terminal truncation mitigates synucleinopathy and neurodegeneration in a transgenic model of multiple system atrophy

Bassil

Fernagut

Bézard

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Multiple system atrophy (MSA) is a sporadic orphan neurodegenerative disorder. No treatment is currently available to slow down the aggressive neurodegenerative process, and patients die within a few years after disease onset. The cytopathological hallmark of MSA is the accumulation of alpha-synuclein (α-syn) aggregates in affected oligodendrocytes. Several studies point to α-syn oligomerization and aggregation as a mediator of neurotoxicity in synucleinopathies including MSA. C-terminal truncation by the inflammatory protease caspase-1 has recently been implicated in the mechanisms that promote aggregation of α-syn in vitro and in neuronal cell models of α-syn toxicity. We present here an in vivo proof of concept of the ability of the caspase-1 inhibitor prodrug VX-765 to mitigate α-syn pathology and to mediate neuroprotection in proteolipid protein α-syn (PLP-SYN) mice, a transgenic mouse model of MSA. PLP-SYN and age-matched wild-type mice were treated for a period of 11 wk with VX-765 or placebo. VX-765 prevented motor deficits in PLP-SYN mice compared with placebo controls. More importantly, VX-765 was able to limit the progressive toxicity of α-syn aggregation by reducing its load in the striatum of PLP-SYN mice. Not only did VX-765 reduce truncated α-syn, but it also decreased its monomeric and oligomeric forms. Finally, VX-765 showed neuroprotective effects by preserving tyrosine hydroxylase-positive neurons in the substantia nigra of PLP-SYN mice. In conclusion, our results suggest that VX-765, a drug that was well tolerated in a 6 wk-long phase II trial in patients with epilepsy, is a promising candidate to achieve disease modification in synucleinopathies by limiting α-syn accumulation.alpha-synuclein | multiple system atrophy | caspase-1 | truncation

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“…The facts that the presence of C-terminally truncated ␣-synuclein in LB of sporadic PD and LB dementia (9,10), the existence of various lengths of the truncated forms of ␣-synuclein in brain (10,11), and the formation of C-terminally truncated ␣-synuclein in A53T transgenic mice that show motor symptoms (12) implicate the probable involvement of endopeptidases in cleaving ␣-synuclein in brains. In addition, about 15% of ␣-synuclein in LB are truncated forms, and incomplete degradation of ␣-synuclein produced highly amyloidogenic fragments (9,13). Recent reports showed that matrix metalloproteinases were able to cleave ␣-synuclein, and MMP3 was the most efficient enzyme among them in cleaving ␣-synuclein into several fragments (14).…”

mentioning

confidence: 99%

Role of Matrix Metalloproteinase 3-mediated α-Synuclein Cleavage in Dopaminergic Cell Death

Choi

Kim

et al. 2011

Journal of Biological Chemistry

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Evidence suggests that the C-terminal truncation of ␣-synuclein is equally important as aggregation of ␣-synuclein in Parkinson disease (PD). Our previous results showed that an endopeptidase, matrix metalloproteinase-3 (MMP3), was induced and activated in dopaminergic (DA) cells upon stress conditions. Here, we report that MMP3 cleaved ␣-synuclein in vitro and in vivo and that ␣-synuclein and MMP3 were co-localized in Lewy bodies (LB) in the postmortem brains of PD patients. Incubation of ␣-synuclein with the catalytic domain of MMP3 (cMMP3) resulted in generation of several peptides, and the peptide profiles of WT ␣-synuclein (WTsyn) and A53T mutant (A53Tsyn) were different. Combined analysis using mass spectrometry and N-terminal determination revealed that MMP3 generated C-terminally truncated peptides of amino acids 1-78, 1-91, and 1-93 and that A53Tsyn produced significantly higher quantities of these peptides. Similar sizes of peptides were detected in N27 DA cells under oxidative stress and RNA interference to knock down MMP3-attenuated peptide generation. Co-overexpression of cMMP3 with either WTsyn or A53Tsyn led to a reduction in Triton X-100-insoluble aggregates and an increase in protofibril-like small aggregates. In addition, overexpression of the 1-93-amino acid peptide in the substantia nigra led to DA neuronal loss without LB-like aggregate formation. The results strongly indicate that MMP3 digestion of ␣-synuclein in DA neurons plays a pivotal role in the progression of PD through modulation of ␣-synuclein in aggregation, LB formation, and neurotoxicity.The epidemiological as well as animal studies suggest that environmental factors, genetic predispositions, and the interplay between the two factors are implicated in the PD 3 pathogenesis (1), although the underlying molecular mechanisms remain largely unknown. ␣-Synuclein is a major component of Lewy bodies (LB), the pathological hallmark of Parkinson disease (2). As expression of three mutant forms of ␣-synuclein, A53T, A30P, and E46K, in the brain (3-5) and increased copy number by duplication or triplication of the wild-type ␣-synuclein gene (6 -8) have been reported in the early onset familial cases of PD, the pathophysiological role of these mutants of ␣-synuclein has been a target of extensive investigations in PD research. The ability of ␣-synuclein to aggregate and form fibrillar deposits has been shown to play a central role in its pathology. The facts that the presence of C-terminally truncated ␣-synuclein in LB of sporadic PD and LB dementia (9, 10), the existence of various lengths of the truncated forms of ␣-synuclein in brain (10, 11), and the formation of C-terminally truncated ␣-synuclein in A53T transgenic mice that show motor symptoms (12) implicate the probable involvement of endopeptidases in cleaving ␣-synuclein in brains. In addition, about 15% of ␣-synuclein in LB are truncated forms, and incomplete degradation of ␣-synuclein produced highly amyloidogenic fragments (9, 13). Recent reports showed that matrix metalloprotei...

show abstract

The solubility of α‐synuclein in multiple system atrophy differs from that of dementia with Lewy bodies and Parkinson's disease

Cited by 206 publications

References 36 publications

The small heat shock protein Hsp27 binds α-synuclein fibrils, preventing elongation and cytotoxicity

The small heat shock protein Hsp27 binds α-synuclein fibrils, preventing elongation and cytotoxicity

Reducing C-terminal truncation mitigates synucleinopathy and neurodegeneration in a transgenic model of multiple system atrophy

Role of Matrix Metalloproteinase 3-mediated α-Synuclein Cleavage in Dopaminergic Cell Death

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