Therapeutic potential of iron modulating drugs in a mouse model of multiple system atrophy

Shukla, Jay J; Stefanova, Nadia; Bush, Ashley I.; McColl, Gawain; Finkelstein, David I.; McAllum, Erin J.

doi:10.1016/j.nbd.2021.105509

Cited by 12 publications

(12 citation statements)

References 60 publications

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“…(3) multiple autonomic centers in the brain and spinal cord of PLP-a-syn mice show selective neuronal loss [87][88][89][90]; (4) nigral and striatal neuronal loss feature the underlying motor pathology in PLP-a-syn mice [78]; (5) olivopontocerebellar pathology can be triggered by mitochondrial or proteolytic stress in the PLP-a-syn mouse [85,86]; (6)(7)(8) the neurodegeneration is mediated through gliosis and neuroinflammatory signaling [18,85,112]; (9) early signs of oligodendroglial and myelin dysfunction [95] are accelerated by proteolytic stress [86]; and (10) iron deposition in the degenerating areas can be identified [102,105]. Created with BioRe nder.…”

Section: Discussionmentioning

confidence: 99%

“…All relevant current MSA models are based on the assumption that pathological a-syn is the cause of MSA neurodegeneration. On one hand, such a-syn models of MSA are advantageous when testing a-syn targeting treatment strategies, because they provide a clear-cut readout of efficacy based on a-syn pathology modulation [98][99][100][101][102][103][104][105]. Furthermore, the a-syn-based models of MSA provide the possibility to screen targeting of other relevant pathways and disease mechanisms downstream of a-syn pathology like neuroinflammation [18,19,78,106,107], neurotrophic disbalance [108,109], epigenetic impairment [110], or demyelination [97].…”

Section: The Msa Transgenic Mousea Preclinical Therapeutic Testbed Fo...mentioning

confidence: 99%

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A Mouse Model of Multiple System Atrophy: Bench to Bedside

Stefanova

2023

Neurotherapeutics

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Multiple system atrophy (MSA) is a rare neurodegenerative disorder with unclear etiology, currently difficult and delayed diagnosis, and rapid progression, leading to disability and lethality within 6 to 9 years after symptom onset. The neuropathology of MSA classifies the disease in the group of a-synucleinopathies together with Parkinson’s disease and other Lewy body disorders, but features specific oligodendroglial inclusions, which are pathognomonic for MSA. MSA has no efficient therapy to date. Development of experimental models is crucial to elucidate the disease mechanisms in progression and to provide a tool for preclinical screening of putative therapies for MSA. In vitro and in vivo models, based on selective neurotoxicity, a-synuclein oligodendroglial overexpression, and strain-specific propagation of a-synuclein fibrils, have been developed, reflecting various facets of MSA pathology. Over the years, the continuous exchange from bench to bedside and backward has been crucial for the advancing of MSA modelling, elucidating MSA pathogenic pathways, and understanding the existing translational gap to successful clinical trials in MSA. The review discusses specifically advantages and limitations of the PLP-a-syn mouse model of MSA, which recapitulates motor and non-motor features of the human disease with underlying striatonigral degeneration, degeneration of autonomic centers, and sensitized olivopontocerebellar system, strikingly mirroring human MSA pathology.

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Section: Discussionmentioning

confidence: 99%

Section: The Msa Transgenic Mousea Preclinical Therapeutic Testbed Fo...mentioning

confidence: 99%

A Mouse Model of Multiple System Atrophy: Bench to Bedside

Stefanova

2023

Neurotherapeutics

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“…The PLP-α-syn mouse model of MSA exhibited an age-and region-dependent increase in brain iron levels and treatment with deferiprone, ceruloplasmin, or ATH434 improved neuronal survival and motor performance and reduced α-syn accumulation in the SNpc. 103,104 Whether muscle iron levels are increased in MSA patients or whether improvements in motor performance with iron-modulating compounds are associated with reduced muscle iron are unknown and deserving of investigation.…”

Section: Pharmacological Interventionsmentioning

confidence: 99%

“…Like PD, MSA patients have increased iron levels in the SNpc and the striatum [S63] and a case study observed iron deposition in the putamen of an MSA‐P patient preceded onset of clinical symptoms by 2 years [S75]. The PLP‐α‐syn mouse model of MSA exhibited an age‐ and region‐dependent increase in brain iron levels and treatment with deferiprone, ceruloplasmin, or ATH434 improved neuronal survival and motor performance and reduced α‐syn accumulation in the SNpc 103,104 . Whether muscle iron levels are increased in MSA patients or whether improvements in motor performance with iron‐modulating compounds are associated with reduced muscle iron are unknown and deserving of investigation.…”

Section: Atypical Parkinsonian Syndromesmentioning

confidence: 99%

Impaired skeletal muscle health in Parkinsonian syndromes: clinical implications, mechanisms and potential treatments

Murphy

Lynch

2023

J cachexia sarcopenia muscle

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There is increasing evidence that neurodegenerative disorders including the Parkinsonian syndromes are associated with impaired skeletal muscle health, manifesting as wasting and weakness. Many of the movement problems, lack of muscle strength and reduction in quality of life that are characteristic of these syndromes can be attributed to impairments in skeletal muscle health, but this concept has been grossly understudied and represents an important area of unmet clinical need. This review describes the changes in skeletal muscle health in idiopathic Parkinson's disease and in two atypical Parkinsonian syndromes, the most aggressive synucleinopathy multiple system atrophy, and the tauopathy progressive supranuclear palsy. The pathogenesis of the skeletal muscle changes is described, including the contribution of impairments to the central and peripheral nervous system and intrinsic alterations. Pharmacological interventions targeting the underlying molecular mechanisms with therapeutic potential to improve skeletal muscle health in affected patients are also discussed. Although little is known about the mechanisms underlying these conditions, current evidence implicates multiple pathways and processes, highlighting the likely need for combination therapies to protect muscle health and emphasizing the merit of personalized interventions for patients with different physical capacities at different stages of their disease. As muscle fatigue is often experienced by patients prior to diagnosis, the identification and measurement of this symptom and related biomarkers to identify early signs of disease require careful interrogation, especially for multiple system atrophy and progressive supranuclear palsy where diagnosis is often made several years after onset of symptoms and only confirmed post‐mortem. We propose a multidisciplinary approach for early diagnosis and implementation of personalized interventions to preserve muscle health and improve quality of life for patients with typical and atypical Parkinsonian syndromes.

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“…Male and female PLP-αsynuclein mice overexpressing human wild-type α-synuclein under the control of the oligodendrocyte-specific proteolipid protein promoter (PLP-αsyn mice) on a C57Bl/6 background were used for all experiments [45] . The mice were housed in a temperature-controlled, pathogen-free environment under a 12-h light/dark cycle at the animal facility of The Florey Institute of Neuroscience and Mental Health and allowed access to standard laboratory chow and water ad libitum.…”

Section: Animalsmentioning

confidence: 99%

Epsin2, a novel target for multiple system atrophy therapy via α-synuclein/FABP7 propagation

Cheng

Wang

Sekimori

et al. 2022

Preprint

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Background: Multiple system atrophy (MSA) is an adult-onset, fatal neurodegenerative disease featured by propagation of misfolded α-synuclein and dysregulation of myelin integrity in central nervous systems (CNS). In our previous study, we identified that fatty acid binding protein 7 (FABP7), one glial protein regulated α-synuclein (α-syn) toxicity and closely related to oligodendrocyte loss. Here, we investigated how FABP7 works in MSA pathological process. Methods: The mouse model of MSA: PLP-hαSyn transgenic mice (PLP-hαSyn mice) were used for understanding the underling role of FABP7 in α-syn aggregation. In vitro, FABP7/α-syn hetero-aggregates were constructed by recombinant human-α-syn and 6X His-tag human-FABP7. By immunohistochemical analyze of brain tissue from PLP-hαSyn mice and aggregates injection mice, we identified the toxicity of aggregates and the region or cell type in brain which aggregates prefer to propagate. Furthermore, through the bioinformatics analysis of MSA patient blood, PLP mouse brain tissue we found candidate proteins related to α-syn propagation. Then, the hypothesis was verified by adeno-associated virus (AAV) knockdown in aggregates injection mice. Findings: In PLP-hαSyn mice, FABP7 also forms hetero-aggregates with α-syn and the FABP7/α-syn hetero-aggregates exhibited higher molecular weight and stronger toxicity than α-syn aggregates both in vitro and in vivo. The same with PLP-hαSyn mice, in the FABP7/α-syn hetero-aggregates injected mice, aggregates prefer to accumulate in oligodendrocyte and purkinje neurons. By bioinformatics analysis we found the protein epsin-2 as a potential receptor which regulate FABP7/α-syn hetero-aggregates propagate to oligodendrocytes and purkinje neurons. In AAV-dependent epsin-2 knock down mice we observed decreased levels of FABP7/α-syn hetero-aggregates in purkinje neurons and oligodendrocytes. Conclusions: These data suggest that epsin-2 is an important potential therapeutic target for MSA via regulating FABP7/α-syn hetero-aggregates propagation. It is very meaningful for further investigation and developing specific inhibitors. Funding: This work was supported by the Strategic Research Program for Brain Sciences from the Japan Agency for Medical Research and Development (JP17dm0107071, JP18dm0107071, JP19dm0107071, and JP20dm0107071).

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Therapeutic potential of iron modulating drugs in a mouse model of multiple system atrophy

Cited by 12 publications

References 60 publications

A Mouse Model of Multiple System Atrophy: Bench to Bedside

A Mouse Model of Multiple System Atrophy: Bench to Bedside

Impaired skeletal muscle health in Parkinsonian syndromes: clinical implications, mechanisms and potential treatments

Epsin2, a novel target for multiple system atrophy therapy via α-synuclein/FABP7 propagation

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