Synapsin III gene silencing redeems alpha-synuclein transgenic mice from Parkinson's disease-like phenotype

Abstract

Fibrillary aggregated a-synuclein (a-syn) deposition in Lewy bodies (LB) characterizes Parkinson's disease (PD) and is believed to trigger dopaminergic synaptic failure and a retrograde terminal-to-cell body neuronal degeneration. We described that the neuronal phosphoprotein synapsin III (Syn III) cooperates with a-syn to regulate dopamine (DA) release and can be found in the insoluble a-syn fibrils composing LB. Moreover, we showed that a-syn aggregates deposition, and the associated onset of synaptic deficits and neuronal degeneration occurring following adeno-associated viral vectors-mediated overexpression of human a-syn in the nigrostriatal system are hindered in Syn III knock out mice. This supports that Syn III facilitates a-syn aggregation. Here, in an interventional experimental design, we found that by inducing the gene silencing of Syn III in human a-syn transgenic mice at PD-like stage with advanced a-syn aggregation and overt striatal synaptic failure, we could lower a-syn aggregates and striatal fibers loss. In parallel, we observed recovery from synaptic vesicles clumping, DA release failure, and motor functions impairment. This supports that Syn III consolidates a-syn aggregates, while its downregulation enables their reduction and redeems the PD-like phenotype. Strategies targeting Syn III could thus constitute a therapeutic option for PD.

Parkinson's disease relevant pathological features are manifested in male Pink1/Parkin deficient rats

“…Using an aggregation specific α-syn antibody, we confirmed that the observed puncta in the striatum were in fact α-syn aggregates. Increasing evidence suggests aggregation of α-syn at the synapse is an early event in PD pathogenesis and is associated with impaired striatal synaptic function and DA neuronal death ( Faustini et al, 2022 ; Srinivasan et al, 2021 ). While PD patients with Parkin mutations rarely exhibit Lewy pathology ( Schneider and Alcalay, 2017 ), only seventeen studies published from 1994 to 2018 have investigated post-mortem brains from such patients with a focus on Lewy body formation and of these eight reported the presence of Lewy bodies and one showed basophilic Lewy body-like inclusion bodies (reviewed in ( Madsen et al, 2021 )).…”

Altered Distribution of SNARE Proteins in Primary Neurons Exposed to Different Alpha-Synuclein Proteoforms

“…First, it facilitates the formation of the SNARE complex, which is essential to neurons as it regulates the fusion of synaptic vesicles to the plasma membrane, leading to neurotransmitter release (Sudhof 2013 ). Second, it regulates neurotransmitter release by restricting synaptic vesicle mobilization and recycling (Faustini et al 2022 ). However, the interplay between the synaptic vesicle release machinery and pathological α-syn remains poorly defined.…”

Can We Treat Neurodegenerative Proteinopathies by Enhancing Protein Degradation?

“…At present, our knowledge of the features of aSyn micro‐aggregates, their trans‐synaptic spreading potential or intrinsic toxicity in PD or DLB is still scarce, but it is likely that their progressive accumulation in the few spared neurons, rather than LB formation, represents the noxious event contributing to neurodegeneration and disease progression. Along these lines, recent reports showed that genetic‐based control of the expression of αSyn synaptic protein partners in the brain of human αSyn transgenic mice at a pathological stage could halt neurodegeneration and restore dopaminergic neuron function and animal motility by reducing the deposition of fibrillary αSyn 50,51 . This suggests that the αSyn fibrils forming microaggregates may constitute a more dynamic and possibly reversible entity than those forming mature LB, because they are destabilized by changes in the αSyn interactome.…”

“…Along these lines, recent reports showed that genetic-based control of the expression of αSyn synaptic protein partners in the brain of human αSyn transgenic mice at a pathological stage could halt neurodegeneration and restore dopaminergic neuron function and animal motility by reducing the deposition of fibrillary αSyn. 50,51 This suggests that the αSyn fibrils forming microaggregates may constitute a more dynamic and possibly reversible entity than those forming mature LB, because they are destabilized by changes in the αSyn interactome. Therefore, it may also be easier to clear them from the brain.…”