Hippocampal α-synuclein and interneurons in Parkinson's disease: Data from human and mouse models

Flores‐Cuadrado, Alicia; Úbeda-Bañón, Isabel; Saiz-Sánchez, Daniel; Rosa-Prieto, Carlos de la; Martı́nez-Marcos, Alino

doi:10.1002/mds.26586

Cited by 28 publications

(27 citation statements)

References 79 publications

(199 reference statements)

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“…Also, the intrinsic dendrites vs. somatostatin-positive axons from distal sites cannot be discarded (Lepousez et al, 2010 ). Interestingly, calcium-binding proteins, but rarely somatostatin, co-localized with α-synuclein, which was in agreement with previous studies (Flores-Cuadrado et al, 2016 , 2017 ).…”

Section: Discussionsupporting

confidence: 93%

Differential Effects of Parkinson’s Disease on Interneuron Subtypes within the Human Anterior Olfactory Nucleus

et al. 2017

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Synucleinopathies (including α-synucleinopathies), which include Parkinson’s disease (PD), manifest themsevles early on (stage 1) in the olfactory system; preferentially in the anterior olfactory nucleus (AON). In particular, the non-motor, early manifestations of PD include hyposmia, which is the partial loss of the sense of smell. The neural basis of hyposmia in PD, however, is poorly understood; but the AON appears to be a key structure in the disease’s progression. We analyzed whether α-synuclein was involved in the differential interneuron vulnerability associated with PD in the retrobulbar, cortical anterior and cortical posterior divisions of the AON. First, we determined the expression of the calcium binding interneuron markers, calretinin, calbindin and parvalbumin, as well as non-calcium binding interneuron marker, somatostatin, in neuronal cell bodies alone (cells/mm2) and in neuronal cell bodies and neurites (% of area fraction) of post-mortem tissue from PD cases and age-matched controls (n = 4 for each) by immunofluorescent confocal microscopy. Results indicated that parvalbumin expression was upregulated in neuronal cell bodies throughout the anterior olfactory nucleus of PD cases compared with controls. Furthermore, there was increased calbindin, calretinin and parvalbumin expression in the cell bodies and neurites of neurons in the retrobulbar division and also increased parvalbumin expression in the neurites of neurons in the cortical division; calretinin expression was also increased in neuronal cell bodies and neurites in the cortical posterior division. Second, we analyzed the co-localization of the above markers with α-synuclein, with results indicating that α-synuclein co-localized with the calcium-binding proteins, but only partially with somatostatin. Taken together, these results indicate differential expression levels among different neural markers in the divisions of the AON in PD cases and point to several possibilities, among them: possible neuroprotective mechanisms of calcium-binding proteins against α-synuclein; and the differential involvement of somatostatin in α-synuclein-positive cell bodies and neurites.

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Section: Discussionsupporting

confidence: 93%

Differential Effects of Parkinson’s Disease on Interneuron Subtypes within the Human Anterior Olfactory Nucleus

et al. 2017

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“…; red). The α‐syn expression was a diffuse, punctate pattern matching that of synaptophysin, consistent with its preferentially presynaptic localization as observed in previous studies . In comparison, FUS‐targeted regions of animals treated with hSNCA‐shRNA had lower α‐syn immunoreactivity.…”

Section: Resultssupporting

confidence: 88%

Noninvasive delivery of an α‐synuclein gene silencing vector with magnetic resonance–guided focused ultrasound

et al. 2018

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Background: The characteristic progression of Lewy pathology in Parkinson’s disease likely involves intercellular exchange and accumulation of misfolded α-synuclein amplified by a prion-like self-templating mechanism. Silencing of the α-synuclein gene could provide long-lasting disease modifying benefits by reducing the requisite substrate for the spreading aggregation. Objectives: Due to poor penetration of viral vectors across the blood-brain barrier, gene therapy for central nervous system disorders requires direct injections into affected brain regions, and invasiveness is further increased by the need for bilateral delivery to multiple brain regions. Here we test a non-invasive approach by combining low intensity MR-guided focused ultrasound and intravenous microbubbles that can transiently increase the access of brain impermeant therapeutic macromolecules to targeted brain regions. Methods: Transgenic mice expressing human α-synuclein were subjected to MR-guided focused ultrasound targeted to four brain regions (hippocampus, substantia nigra, olfactory bulb, and dorsal motor nucleus) in tandem with intravenous microbubbles and an adeno-associated virus serotype 9 vector bearing a short hairpin RNA sequence targeting the α-synuclein gene. Results: One month following treatment, α-synuclein immunoreactivity was decreased in targeted brain regions, whereas other neuronal markers such as synaptophysin or tyrosine hydroxylase were unchanged, and cell death and glial activation remained at basal levels. Conclusions: These results demonstrate that MR-guided focused ultrasound can effectively, non-invasively, and simultaneously deliver viral vectors targeting α-synuclein to multiple brain areas. Importantly, this approach may be useful to alter the progression of Lewy pathology along selected neuronal pathways, particularly as prodromal PD markers improve early diagnoses.

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“…Physiologically, α-synuclein is localized at presynaptic terminals throughout the mammalian brain and is involved in the generation and maintenance of synapses [27–29]. In the hippocampal synapse, α-synuclein expression is highly concentrated in the granular and polymorphic layers of the dentate gyrus (DG) as well as in the CA2 and CA3 fields [30]. In particular, α-synuclein is found to be localized at excitatory presynapses and co-expressed with vesicular glutamate transporter1 (vGluT1), an excitatory presynaptic marker [31, 32].…”

Section: Introductionmentioning

confidence: 99%

Ginsenoside Rb1 prevents MPTP-induced changes in hippocampal memory via regulation of the α-synuclein/PSD-95 pathway

Meng

Liu

et al. 2019

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Memory deficiency is a common non-motor symptom of Parkinson’s disease (PD), and conventionally, α-synuclein is considered to be an important biomarker for both motor and cognitive characteristics attributed to PD. However, the role of physiological α-synuclein in cognitive impairment remains undetermined. Ginsenoside Rb1 has been shown to protect dopaminergic neurons (DA) from death and inhibit α-synuclein fibrillation and toxicity in vitro . Our recent study also revealed that ginsenoside Rb1 ameliorates motor deficits and prevents DA neuron death via upregulating glutamate transporter GLT-1 in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Whether Rb1 can improve memory deficiency and the underlying mechanism is still unknown. In this study, we found that Rb1 can prevent the spatial learning and memory deficits, increase long-term potentiation (LTP) and hippocampal glutamatergic transmission in the MPTP mouse model. The underlying neuroprotective mechanism of Rb1-improved synaptic plasticity involves Rb1 promoting hippocampal CA3 α-synuclein expression, restoring the glutamate in the CA3-schaffer collateral-CA1 pathway, and sequentially increasing postsynaptic density-95 (PSD-95) expression. Thus, we provide evidence that Rb1 modulates memory function, synaptic plasticity, and excitatory transmission via the trans-synaptic α-synuclein/PSD-95 pathway. Our findings suggest that Rb1 may serve as a functional drug in treating the memory deficiency in PD.

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Hippocampal α-synuclein and interneurons in Parkinson's disease: Data from human and mouse models

Abstract: The differential α-synucleinopathy of hippocampal interneuron populations may help in the study of mechanisms of protein aggregation and progression relevant to PD and PD dementia. © 2016 International Parkinson and Movement Disorder Society.

Cited by 28 publications

References 79 publications

Differential Effects of Parkinson’s Disease on Interneuron Subtypes within the Human Anterior Olfactory Nucleus

Differential Effects of Parkinson’s Disease on Interneuron Subtypes within the Human Anterior Olfactory Nucleus

Noninvasive delivery of an α‐synuclein gene silencing vector with magnetic resonance–guided focused ultrasound

Ginsenoside Rb1 prevents MPTP-induced changes in hippocampal memory via regulation of the α-synuclein/PSD-95 pathway

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