Accumulation of oligomer-prone α-synuclein exacerbates synaptic and neuronal degeneration in vivo

Abstract

In Parkinson's disease and dementia with Lewy bodies, α-synuclein aggregates to form oligomers and fibrils; however, the precise nature of the toxic α-synuclein species remains unclear. A number of synthetic α-synuclein mutations were recently created (E57K and E35K) that produce species of α-synuclein that preferentially form oligomers and increase α-synuclein-mediated toxicity. We have shown that acute lentiviral expression of α-synuclein E57K leads to the degeneration of dopaminergic neurons; however, the effects of chronic expression of oligomer-prone α-synuclein in synapses throughout the brain have not been investigated. Such a study could provide insight into the possible mechanism(s) through which accumulation of α-synuclein oligomers in the synapse leads to neurodegeneration. For this purpose, we compared the patterns of neurodegeneration and synaptic damage between a newly generated mThy-1 α-synuclein E57K transgenic mouse model that is prone to forming oligomers and the mThy-1 α-synuclein wild-type mouse model (Line 61), which accumulates various forms of α-synuclein. Three lines of α-synuclein E57K (Lines 9, 16 and 54) were generated and compared with the wild-type. The α-synuclein E57K Lines 9 and 16 were higher expressings of α-synuclein, similar to α-synuclein wild-type Line 61, and Line 54 was a low expressing of α-synuclein compared to Line 61. By immunoblot analysis, the higher-expressing α-synuclein E57K transgenic mice showed abundant oligomeric, but not fibrillar, α-synuclein whereas lower-expressing mice accumulated monomeric α-synuclein. Monomers, oligomers, and fibrils were present in α-synuclein wild-type Line 61. Immunohistochemical and ultrastructural analyses demonstrated that α-synuclein accumulated in the synapses but not in the neuronal cells bodies, which was different from the α-synuclein wild-type Line 61, which accumulates α-synuclein in the soma. Compared to non-transgenic and lower-expressing mice, the higher-expressing α-synuclein E57K mice displayed synaptic and dendritic loss, reduced levels of synapsin 1 and synaptic vesicles, and behavioural deficits. Similar alterations, but to a lesser extent, were seen in the α-synuclein wild-type mice. Moreover, although the oligomer-prone α-synuclein mice displayed neurodegeneration in the frontal cortex and hippocampus, the α-synuclein wild-type only displayed neuronal loss in the hippocampus. These results support the hypothesis that accumulating oligomeric α-synuclein may mediate early synaptic pathology in Parkinson's disease and dementia with Lewy bodies by disrupting synaptic vesicles. This oligomer-prone model might be useful for evaluating therapies directed at oligomer reduction.

Impaired synaptic function is linked to cognition in Parkinson's disease

“…Although we find strong links to A β , a reverse causality cannot be excluded, in that synaptic dysfunction could be due to presynaptic α ‐synuclein aggregates slightly reducing A β in proportion to the degree of α ‐synuclein‐dependent neurodegeneration 5, 45. Alternatively, defective presynaptic proteolysis and lysosomal degradation could affect both A β and α ‐synuclein metabolism 7, 8, 46.…”

Selective lowering of synapsins induced by oligomeric α-synuclein exacerbates memory deficits

“…The disease significance to this observation is unclear at this time because of the small numbers of brain specimens composing all three categories (LB509 + , A11 + , and LB509/A11 + ) and because of the creation of necessary cut-offs, but certainly warrants larger studies to examine the functional role of these entities of αSyn. Although other groups have provided evidence that ∼35-kDa SDSresistant αSyn dimers can be detected in brain tissue (24,38,39), we speculate that the unique experimental biological specimens used (i.e., human brain tissue with elevated expression of αSyn combined with an absence of LB pathology) allowed us to detect apparent multimers of 14-and 17-kDa αSyn monomers.…”

Molecular neuropathology of the synapse in sheep with CLN5 Batten disease

“…2011; Rockenstein et al. 2014). Changes in α ‐synuclein have been reported in many studies of Batten disease, particularly in CLN1 and CLN10 (cathepsin D) deficient mice (Cullen et al.…”