Increased Expression of Alpha-, Beta-, and Gamma-Synucleins in Brainstem Regions of a Non-Human Primate Model of Parkinson’s Disease

Abstract

Parkinson’s disease (PD) is characterized by cell loss in the substantia nigra and the presence of alpha-synuclein (α-syn)-containing neuronal Lewy bodies. While α-syn has received major interest in the pathogenesis of PD, the function of beta- and gamma-synucleins (β-syn and γ-syn, respectively) is not really known. Yet, these proteins are members of the same family and also concentrated in neuronal terminals. The current preclinical study investigated the expression levels of α-, β-, and γ-synucleins in brainstem regions involved in PD physiopathology. We analyzed synuclein expression in the substantia nigra, raphe nuclei, pedunculopontine nucleus, and locus coeruleus from control and parkinsonian (by MPTP) macaques. MPTP-intoxicated monkeys developed a more or less severe parkinsonian score and were sacrificed after a variable post-MPTP period ranging from 1 to 20 months. The expression of the three synucleins was increased in the substantia nigra after MPTP, and this increase correlates positively, although not very strongly, with cell loss and motor score and not with the time elapsed after intoxication. In the dorsal raphe nucleus, the expression of the three synucleins was also increased, but only α- and γ-Syn are linked to the motor score and associated cell loss. Finally, although no change in synuclein expression was demonstrated in the locus coeruleus after MPTP, we found increased expression levels of γ-Syn, which are only correlated with cell loss in the pedunculopontine nucleus. Altogether, our data suggest that these proteins may play a key role in brainstem regions and mesencephalic tegmentum. Given the involvement of these brain regions in non-motor symptoms of PD, these data also strengthen the relevance of the MPTP macaque model of PD, which exhibits pathological changes beyond nigral DA cell loss and α-synucleinopathy.

Right vagus nerve stimulation improves motor behavior by exerting neuroprotective effects in Parkinson’s disease rats

“…Several limitations have to be acknowledged in this study. First, current studies (13,30) have shown the association between vagus nerve and the midbrain dopaminergic neurons. Nevertheless, the correlation between vagus nerve and neuron network in other locations has not been extensively studied and validated.…”

“…In PD, the degeneration and loss of dopaminergic neurons in the brain are closely related to the abnormal accumulation of α-synuclein. The increased expression of α-synuclein in the midbrain dopaminergic neurons is positively correlated with the severity of movement disorders in PD ( 30 ). The translocation of dopamine to synaptic vesicles by VMAT2 prevents the formation of neurotoxic derivatives of dopamine in the cytosol ( 31 - 33 ).…”

Synucleins: New Data on Misfolding, Aggregation and Role in Diseases

“…The overwhelming majority of publications on synucleins are dedicated to α-synuclein due to its involvement in Parkinson’s disease (PD) and other synucleinopathies. Yet, two other proteins β- and γ-synucleins belonging to the same family are localized predominantly in neuronal terminals and implicated in the long-term modulation and preservation of nerve terminal function and dopamine homeostasis [ 7 ]. As a result, they deserve more attention to better understand the functionality of nervous system and role in carcinogenesis.…”

“…Examination of synucleins in a non-human primate model of PD showed that the expression of all three members of the family was increased in the substantia nigra after treatment with prodrug to the neurotoxin-1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). This increase correlates positively with the loss of cells and motor score [ 7 ]. The expression of the three types of synucleins was also increased in the dorsal raphe nucleus, but only α- and γ-synucleins are associated with the loss of cells and cell loss.…”

“…The expression of the three types of synucleins was also increased in the dorsal raphe nucleus, but only α- and γ-synucleins are associated with the loss of cells and cell loss. The authors conclude that MPTP treatment mainly affects the expression level of α-synuclein and γ-synucleins and, to a lesser extent, β-synuclein levels and suggest that the three members of the synuclein family participate in the regulation of monoaminergic transmission [ 7 ].…”