Region‐<scp>S</scp>pecific <scp>A</scp>lterations of <scp>M</scp>atrix <scp>M</scp>etalloproteinase <scp>A</scp>ctivity in <scp>M</scp>ultiple <scp>S</scp>ystem <scp>A</scp>trophy

Bassil, Fares; Monvoisin, Arnaud; Canron, Marie‐Hélène; Vital, Anne; Meissner, Wassilios G.; Tison, François; Fernagut, Pierre‐Olivier

doi:10.1002/mds.26329

Cited by 8 publications

(4 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…More importantly, studies assessing α-syn pathology in the brain should assess the structure-dependent weight/contribution of different proteases known to cleave α-syn in the brain, thereby leading to a better understanding of the effect of protease inhibitors in the brain. In this regard, we have previously shown a region-dependent alteration/expression of MMPs in the putamen and cortex of MSA patients (55). MMPs have been previously shown to cleave α-syn, thereby producing truncated forms (52,54).…”

Section: Discussionmentioning

confidence: 88%

“…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%

See 1 more Smart Citation

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.

Self Cite

View full text Add to dashboard Cite

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

show abstract

Section: Discussionmentioning

confidence: 88%

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.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Changes in MBP levels in MSA brain suggest myelin lipid dysfunction [ 246, 469, 470 ], which together with aberration in protein distribution may lead to myelin deficit [ 471 ], a crucial pathomechanism in MSA [ 172 ]. Elevated matrix metalloproteinase activity may also contribute to the disease process by promoting blood-brain barrier dysfunction and myelin degeneration [ 472 ]. Oligodendroglial dysfunction supports the notion that neurodegeneration may occur secondary to demyelination and lack of trophic support by GCI-bearing oligodendroglia [ 232 ], but the causative mechanisms of demyelination are not yet fully understood.…”

Section: Pathogenesismentioning

confidence: 99%

Multiple System Atrophy: An Oligodendroglioneural Synucleinopathy1

Jellinger¹

2018

JAD

162

142

View full text Add to dashboard Cite

Multiple system atrophy (MSA) is an orphan, fatal, adult-onset neurodegenerative disorder of uncertain etiology that is clinically characterized by various combinations of parkinsonism, cerebellar, autonomic, and motor dysfunction. MSA is an α-synucleinopathy with specific glioneuronal degeneration involving striatonigral, olivopontocerebellar, and autonomic nervous systems but also other parts of the central and peripheral nervous systems. The major clinical variants correlate with the morphologic phenotypes of striatonigral degeneration (MSA-P) and olivopontocerebellar atrophy (MSA-C). While our knowledge of the molecular pathogenesis of this devastating disease is still incomplete, updated consensus criteria and combined fluid and imaging biomarkers have increased its diagnostic accuracy. The neuropathologic hallmark of this unique proteinopathy is the deposition of aberrant α-synuclein in both glia (mainly oligodendroglia) and neurons forming glial and neuronal cytoplasmic inclusions that cause cell dysfunction and demise. In addition, there is widespread demyelination, the pathogenesis of which is not fully understood. The pathogenesis of MSA is characterized by propagation of misfolded α-synuclein from neurons to oligodendroglia and cell-to-cell spreading in a “prion-like” manner, oxidative stress, proteasomal and mitochondrial dysfunction, dysregulation of myelin lipids, decreased neurotrophic factors, neuroinflammation, and energy failure. The combination of these mechanisms finally results in a system-specific pattern of neurodegeneration and a multisystem involvement that are specific for MSA. Despite several pharmacological approaches in MSA models, addressing these pathogenic mechanisms, no effective neuroprotective nor disease-modifying therapeutic strategies are currently available. Multidisciplinary research to elucidate the genetic and molecular background of the deleterious cycle of noxious processes, to develop reliable biomarkers and targets for effective treatment of this hitherto incurable disorder is urgently needed.

show abstract

“…Changes in MBP levels in MSA brains suggest myelin lipid dysfunction and instability 77,101,102 , which, together with an aberration in protein distribution may lead to myelin dysfunction in MSA 103 . Region-specific increased matrix metalloproteinase activity may contribute to the disease progress by promoting blood-brain barrier dysfunction and myelin degradation 104 .…”

Section: α-Synuclein In Msamentioning

confidence: 99%

Recent advances in multiple system atrophy

Jellinger¹

2016

J Neurol Neuromedicine

View full text Add to dashboard Cite

Multiple system atrophy (MSA) is a fatal orphan neurodegenerative disorder that manifests with autonomic, parkinsonian, cerebellar, and pyramidal features. It is characterized by the accumulation of misfolded α-synuclein (αSyn) in oligodendroglia and neurons, affecting multiple parts of the central, autonomic and perípheral system. Both the etiology and pathogenesis of MSA are unknown, although a genetic component has been proposed. Accumulation of aberrant αSyn in oligodendrocytes, preceded by relocation of p25α protein from myelin into oligodendroglia, results in the formation of insoluble glial cytoplasmic inclusions (GCIs). These changes are associated with proteasomal, mitochondrial and lipid transport dysfunction, oxidative stress, reduced trophic transport, neuroinflammation and other noxious factors. Their interaction induces dysfunction of the oligodendroglial-myelin-axon-neuron complex, resulting in the system-specific pattern of neurodegeneration characterizing MSA as a synucleinopathy with oligodendroglio-neuronopathy. Propagation of modified toxic αSyn species from neurons to oligodendroglia by "prion-like" transfer and its spreading to associate neuronal pathways result in multi-system involvement. No reliable biomarkers are currently available for the clinical diagnosis and prognosis of MSA and neither effective neuroprotective nor disease-modifying therapies of MSA are available, although novel treatment strategies targeting αSyn are under discussion. Multidisciplinary research to elucidate the genetic and molecular background of the deleterious cycle of noxious processes to develop reliable diagnostic biomarkers and to deliver targets for effective treatment of this hitherto incurable disorder is urgently needed.

show abstract

Region‐Specific Alterations of Matrix Metalloproteinase Activity in Multiple System Atrophy

Cited by 8 publications

References 64 publications

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

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

Multiple System Atrophy: An Oligodendroglioneural Synucleinopathy1

Recent advances in multiple system atrophy

Contact Info

Product

Resources

About