Early synaptic dysfunction induced by α-synuclein in a rat model of Parkinson’s disease

Phan, Jenny-Ann; Stokholm, Kathrine; Zarȩba-Pasławska, Justyna; Jakobsen, Steen; Vang, Kim; Gjedde, Albert; Landau, Anne M.; Romero‐Ramos, Marina

doi:10.1038/s41598-017-06724-9

Cited by 68 publications

(63 citation statements)

References 75 publications

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“…In our study, mutant α‐syn was overexpressed in the SN of the minipig brain to generate a large animal model with PD pathology. This α‐syn overexpression approach extends similar studies in mice, rats, and marmosets where recombinant adeno‐associated viral (rAAV) vectors encoding wild‐type or mutant human α‐syn genes were inoculated into nigral dopamine neurons (Kirik et al, ; Maingay, Romero‐Ramos, & Kirik, ; Phan et al, ; Ulusoy, Decressac, Kirik, & Bjorklund, ). These transduction studies led to abnormal accumulation and aggregation of α‐syn associated with loss of dopaminergic function, axonal pathology, and progressive neurodegeneration of tyrosine hydroxylase (TH)‐positive neurons in the SN (Kirik et al, , ; van der Putten et al, ).…”

Section: Introductionsupporting

confidence: 56%

In vivo quantification of glial activation in minipigs overexpressing human α‐synuclein

Lillethorup

Glud

Landeck

et al. 2018

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Parkinson's disease is characterized by a progressive loss of substantia nigra (SN) dopaminergic neurons and the formation of Lewy bodies containing accumulated alpha-synuclein (α-syn). The pathology of Parkinson's disease is associated with neuroinflammatory microglial activation, which may contribute to the ongoing neurodegeneration. This study investigates the in vivo microglial and dopaminergic response to overexpression of α-syn. We used positron emission tomography (PET) and the 18 kDa translocator protein radioligand, [ C](R)PK11195, to image brain microglial activation and (+)-α-[ C]dihydrotetrabenazine ([ C]DTBZ), to measure vesicular monoamine transporter 2 (VMAT2) availability in Göttingen minipigs following injection with recombinant adeno-associated virus (rAAV) vectors expressing either mutant A53T α-syn or green fluorescent protein (GFP) into the SN (4 rAAV-α-syn, 4 rAAV-GFP, 5 non-injected control minipigs). We performed motor symptom assessment and immunohistochemical examination of tyrosine hydroxylase (TH) and transgene expression. Expression of GFP and α-syn was observed at the SN injection site and in the striatum. We observed no motor symptoms or changes in striatal [ C]DTBZ binding potential in vivo or striatal or SN TH staining in vitro between the groups. The mean [ C](R)PK11195 total volume of distribution was significantly higher in the basal ganglia and cortical areas of the α-syn group than the control animals. We conclude that mutant α-syn expression in the SN resulted in microglial activation in multiple sub- and cortical regions, while it did not affect TH stains or VMAT2 availability. Our data suggest that microglial activation constitutes an early response to accumulation of α-syn in the absence of dopamine neuron degeneration.

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Section: Introductionsupporting

confidence: 56%

In vivo quantification of glial activation in minipigs overexpressing human α‐synuclein

Lillethorup

Glud

Landeck

et al. 2018

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“…An increase in subcortical and cortical LB pathology has been observed in major depressive disorder , as well as in amygdala in AD cases with a history of depression . Alpha‐synuclein interaction with dopamine metabolism and transmission may have important implications not only in neuronal loss and motor symptoms , but also through development of depressive symptoms in LBD. Dysfunction in striatal connectivity with limbic and cortical areas is suggested to underpin many neuropsychiatric symptoms in LBD , supported by the strong interaction of mesolimbic circuits with emotional processing .…”

Section: Discussionmentioning

confidence: 99%

Degeneration of dopaminergic circuitry influences depressive symptoms in Lewy body disorders

et al. 2019

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Aims Depression is commonly observed even in prodromal stages of Lewy body disorders (LBD), and is associated with cognitive impairment and a faster rate of cognitive decline. Given the role of dopamine in the development of movement disorders, but also in motivation and reward, we investigated neurodegenerative pathology in dopaminergic circuitry in Parkinson's disease (PD), PD with dementia (PDD) and dementia with Lewy bodies (DLB) patients in relation to depressive symptoms. Methods α‐synuclein, hyperphosphorylated tau and amyloid‐beta pathology was assessed in 17 DLB, 14 PDD and 8 PD cases within striatal and midbrain subregions, with neuronal cell density assessed in substantia nigra and ventral tegmental area. Additionally, we used a structural equation modeling (SEM) approach to investigate the extent to which brain connectivity might influence the deposition of pathological proteins within dopaminergic pathways. Results A significantly higher α‐synuclein burden was observed in the substantia nigra (P = 0.006), ventral tegmental area (P = 0.011) and nucleus accumbens (P = 0.031) in LBD patients with depression. Significant negative correlations were observed between cell density in substantia nigra with Lewy body (LB) Braak stage (P = 0.013), whereas cell density in ventral tegmental area showed negative correlations with LB Braak stage (P = 0.026) and neurofibrillary tangle Braak stage (P = 0.007). Conclusions Dopaminergic α‐synuclein pathology appears to drive depression. Selective targeting of dopaminergic pathways may therefore provide symptomatic relief for depressive symptoms in LBD patients.

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“…α-synuclein is a neuronal protein mainly localized at synaptic sites. Its physiological functions seem to be mostly related with regulation of neurotransmitter release and recycle, as it modulates the size, assembly, and release of synaptic vesicle pools (Murphy et al, 2000;Burre, 2015;Fusco et al, 2016), neurotransmitter reuptake (Burre, 2015;Longhena et al, 2019), exocytotic fusion pore dilation (Logan et al, 2017), and neurotransmitter vesicular uptake (Guo et al, 2008;Pifl et al, 2014;Phan et al, 2017). Remarkably, the multiplicity of α-syn interactions at synaptic sites, coupled with its intrinsic structural plasticity, can account for the cardinal role of the protein at terminals (Bendor et al, 2013;Longhena et al, 2019;Sulzer and Edwards, 2019).…”

Section: α-Synuclein: Physiological Function and Role In Pdmentioning

confidence: 99%

Nuclear Factor-κB Dysregulation and α-Synuclein Pathology: Critical Interplay in the Pathogenesis of Parkinson’s Disease

Bellucci

Bubacco

Longhena

et al. 2020

Front. Aging Neurosci.

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The loss of dopaminergic neurons of the nigrostriatal system underlies the onset of the typical motor symptoms of Parkinson's disease (PD). Lewy bodies (LB) and Lewy neurites (LN), proteinaceous inclusions mainly composed of insoluble α-synuclein (α-syn) fibrils are key neuropathological hallmarks of the brain of affected patients. Compelling evidence supports that in the early prodromal phases of PD, synaptic terminal and axonal alterations initiate and drive a retrograde degeneration process culminating with the loss of nigral dopaminergic neurons. This notwithstanding, the molecular triggers remain to be fully elucidated. Although it has been shown that α-syn fibrillary aggregation can induce early synaptic and axonal impairment and cause nigrostriatal degeneration, we still ignore how and why α-syn fibrillation begins. Nuclear factor-κB (NF-κB) transcription factors, key regulators of inflammation and apoptosis, are involved in the brain programming of systemic aging as well as in the pathogenesis of several neurodegenerative diseases. The NF-κB family of factors consists of five different subunits (c-Rel, p65/RelA, p50, RelB, and p52), which combine to form transcriptionally active dimers. Different findings point out a role of RelA in PD. Interestingly, the nuclear content of RelA is abnormally increased in nigral dopamine (DA) neurons and glial cells of PD patients. Inhibition of RelA exert neuroprotection against (1-methyl-4-phenyl-1,2,3,6tetrahydropyridine) MPTP and 1-methyl-4-phenylpyridinium (MPP+) toxicity, suggesting that this factor decreases neuronal resilience. Conversely, the c-Rel subunit can exert neuroprotective actions. We recently described that mice deficient for c-Rel develop a PD-like motor and non-motor phenotype characterized by progressive brain α-syn accumulation and early synaptic changes preceding the frank loss of nigrostriatal neurons. This evidence supports that dysregulations in this transcription factors may be involved in the onset of PD. This review highlights observations supporting a possible interplay between NF-κB dysregulation and α-syn pathology in PD, with the aim to disclose novel potential mechanisms involved in the pathogenesis of this disorder.

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Early synaptic dysfunction induced by α-synuclein in a rat model of Parkinson’s disease

Cited by 68 publications

References 75 publications

In vivo quantification of glial activation in minipigs overexpressing human α‐synuclein

In vivo quantification of glial activation in minipigs overexpressing human α‐synuclein

Degeneration of dopaminergic circuitry influences depressive symptoms in Lewy body disorders

Nuclear Factor-κB Dysregulation and α-Synuclein Pathology: Critical Interplay in the Pathogenesis of Parkinson’s Disease

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