Neuroprotection by Epigenetic Modulation in a Transgenic Model of Multiple System Atrophy

Sturm, Edith; Fellner, Lisa; Krismer, Florian; Poewe, Werner; Wenning, Gregor K.; Stefanova, Nadia

doi:10.1007/s13311-016-0447-1

Cited by 17 publications

(13 citation statements)

References 35 publications

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“…Genotyping was performed as previously described. 42 Mice of both sexes were investigated at the ages of 8 to 10 weeks (adult) and 1 year (aged). All experiments were performed according to the ethical guidelines with the permission of the Austrian Federal Ministry of Science and Research (breeding permission BMWF-66.011/0120-II/3b/2013).…”

Section: Animalsmentioning

confidence: 99%

Assessment of the Retina of Plp-α-Syn Mice as a Model for Studying Synuclein-Dependent Diseases

Kaehler

Seitter

Sandbichler

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Synucleinopathies such as multiple system atrophy (MSA) and Parkinson's disease are associated with a variety of visual symptoms. Functional and morphological retinal aberrations are therefore supposed to be valuable biomarkers for these neurodegenerative diseases. This study examined the retinal morphology and functionality resulting from human α-synuclein (α-Syn) overexpression in the transgenic Plp-α-Syn mouse model. METHODS. Immunohistochemistry on retinal sections and whole-mounts was performed on 8-to 11-week-old and 12-month-old Plp-α-Syn mice and C57BL/6N controls. Quantitative RT-PCR experiments were performed to study the expression of endogenous and human α-Syn and tyrosine hydroxylase (TH). We confirmed the presence of human α-Syn in the retina in western blot analyses. Multi-electrode array (MEA) analyses from light-stimulated whole-mounted retinas were used to investigate their functionality. RESULTS. Biochemical and immunohistochemical analyses showed human α-Syn in the retina of Plp-α-Syn mice. We found distinct staining in different retinal cell layers, most abundantly in rod bipolar cells of the peripheral retina. In the periphery, we also observed a trend toward a decline in the number of retinal ganglion cells. The number of TH+ neurons was unaffected in this human α-Syn overexpression model. MEA recordings showed that Plp-α-Syn retinas were functional but exhibited mild alterations in dim light conditions. CONCLUSIONS. Together, these findings implicate an impairment of retinal neurons in the Plp-α-Syn mouse. The phenotype partly relates to retinal deficits reported in MSA patients. We further propose the suitability of the Plp-α-Syn retina as a biological model to study synuclein-mediated mechanisms.

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Section: Animalsmentioning

confidence: 99%

Assessment of the Retina of Plp-α-Syn Mice as a Model for Studying Synuclein-Dependent Diseases

Kaehler

Seitter

Sandbichler

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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“…Gait analysis. Gait analysis was performed 10 weeks after treatment, as described previously (33). Briefly, a DigiGait Analysis System (Mouse Specifics) was used.…”

Section: Assessment Of Motor Functionmentioning

confidence: 99%

Shock waves promote spinal cord repair via TLR3

Gollmann‐Tepeköylü¹,

Nägele²,

Graber³

et al. 2020

JCI Insight

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“…Such neurotoxic effects were rescued upon the treatment with an HDAC inhibitor (Kontopoulos et al, 2006 ). Another study in a mouse model of MSA showed that histone deacetylation inhibition presented a neuroprotective role in the pathogenesis of MSA-like neurodegeneration (Sturm et al, 2016 ).…”

Section: The Role Of Hdac6 In α-Synucleinopathiesmentioning

confidence: 99%

Histone Deacetylase 6 and the Disease Mechanisms of α-Synucleinopathies

Lemos

Stefanova

2020

Front. Synaptic Neurosci.

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The abnormal accumulation of α-Synuclein (α-Syn) is a prominent pathological feature in a group of diseases called α-Synucleinopathies, such as Parkinson’s disease, dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). The formation of Lewy bodies (LBs) and glial cytoplasmic inclusions (GCIs) in neurons and oligodendrocytes, respectively, is highly investigated. However, the molecular mechanisms behind α-Syn improper folding and aggregation remain unclear. Histone deacetylase 6 (HDAC6) is a Class II deacetylase, containing two active catalytic domains and a ubiquitin-binding domain. The properties of HDAC6 and its exclusive cytoplasmic localization allow HDAC6 to modulate the microtubule dynamics, acting as a specific α-tubulin deacetylase. Also, HDAC6 can bind ubiquitinated proteins, facilitating the formation of the aggresome, a cellular defense mechanism to cope with higher levels of misfolded proteins. Several studies report that the aggresome shares similarities in size and composition with LBs and GCIs. HDAC6 is found to co-localize with α-Syn in neurons and in oligodendrocytes, together with other aggresome-related proteins. The involvement of HDAC6 in several neurodegenerative diseases is already under discussion, however, the results obtained by modulating HDAC6 activity are not entirely conclusive. The main goal of this review is to summarize and critically discuss previous in vitro and in vivo data regarding the specific role of HDAC6 in the context of α-Syn accumulation and protein aggregation in α-Synucleinopathies.

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Neuroprotection by Epigenetic Modulation in a Transgenic Model of Multiple System Atrophy

Cited by 17 publications

References 35 publications

Assessment of the Retina of Plp-α-Syn Mice as a Model for Studying Synuclein-Dependent Diseases

Assessment of the Retina of Plp-α-Syn Mice as a Model for Studying Synuclein-Dependent Diseases

Shock waves promote spinal cord repair via TLR3

Histone Deacetylase 6 and the Disease Mechanisms of α-Synucleinopathies

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