The pathological aggregation and deposition of α-synuclein in proteinaceous inclusions represent a feature of a group of neurodegenerative disorders called α-synucleinopathies. They comprise a diverse group of proteinopathies such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Alpha-synuclein is a presynaptic protein that is involved in the control of dopaminergic synapses and the clustering of synaptic vesicles, its conformation can be easily disturbed by small pH variations, by the presence of reactive oxygen species and by post translational modifications, thus leading to the toxic aggregation of the protein. Among α-synucleinopathies, in PD and DLB, α-synuclein aggregates in intracellular and intraneuritic inclusions called Lewy bodies (LB) and Lewy neurites (LN). Recently, we demonstrated that α-synuclein interacts and cooperates with the synaptic phosphoprotein synapsin III, a crucial regulator of dopamine striatal synaptic release. Here we discovered by transmitted electron microscopy (TEM) that synapsin III is the only synapsin isoform that is present in α-synuclein-positive fibrils extracted from the LB present substantia nigra of patients affected by PD. In addition, we found that LB and LN in the substantia nigra of PD patients and in the hippocampus of a DLB subject, exhibited a marked immunopositivity for synapsin III. We found a significant accumulation of synapsin III in the caudate/putamen of patients affected by PD when compared to matched controls. Moreover, the in situ PLA revealed that α-synuclein and synapsin III are tightly associated in the brain of both patients and control subjects. In particular, a strong PLA-positive signal was detected in LB inclusions found in the brain of PD and DLB patients. Co-immunoprecipitation studies confirmed that synapsin III interacted with a high moleculas species of α-synuclein both in the brain and in the CSF of patients affected by α-synucleinopaties. Our findings suggest that synapsin III may play an important role in the onset synaptic dysfunction in α-synucleinopathies. The existence of a cooperative pathological interaction between α-synuclein and synapsin III in the pathogenesis of this class of disorders deserves further investigation.
Synapsin III is a key component of α-synuclein fibrils in Lewy bodies of Parkinson’s disease and dementia with Lewy bodies,
Longhena F.;Faustini G.;Zaltieri M.;Porrini V.;Poliani P. L.;Missale C.;Borroni B.;Padovani A.;Pizzi M.;Spano PF.;Bellucci A.
2017-01-01
Abstract
The pathological aggregation and deposition of α-synuclein in proteinaceous inclusions represent a feature of a group of neurodegenerative disorders called α-synucleinopathies. They comprise a diverse group of proteinopathies such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Alpha-synuclein is a presynaptic protein that is involved in the control of dopaminergic synapses and the clustering of synaptic vesicles, its conformation can be easily disturbed by small pH variations, by the presence of reactive oxygen species and by post translational modifications, thus leading to the toxic aggregation of the protein. Among α-synucleinopathies, in PD and DLB, α-synuclein aggregates in intracellular and intraneuritic inclusions called Lewy bodies (LB) and Lewy neurites (LN). Recently, we demonstrated that α-synuclein interacts and cooperates with the synaptic phosphoprotein synapsin III, a crucial regulator of dopamine striatal synaptic release. Here we discovered by transmitted electron microscopy (TEM) that synapsin III is the only synapsin isoform that is present in α-synuclein-positive fibrils extracted from the LB present substantia nigra of patients affected by PD. In addition, we found that LB and LN in the substantia nigra of PD patients and in the hippocampus of a DLB subject, exhibited a marked immunopositivity for synapsin III. We found a significant accumulation of synapsin III in the caudate/putamen of patients affected by PD when compared to matched controls. Moreover, the in situ PLA revealed that α-synuclein and synapsin III are tightly associated in the brain of both patients and control subjects. In particular, a strong PLA-positive signal was detected in LB inclusions found in the brain of PD and DLB patients. Co-immunoprecipitation studies confirmed that synapsin III interacted with a high moleculas species of α-synuclein both in the brain and in the CSF of patients affected by α-synucleinopaties. Our findings suggest that synapsin III may play an important role in the onset synaptic dysfunction in α-synucleinopathies. The existence of a cooperative pathological interaction between α-synuclein and synapsin III in the pathogenesis of this class of disorders deserves further investigation.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
