Abstract
BackgroundAccumulation of alpha-synuclein (α-syn) is a main pathological hallmark of Parkinson’s and related diseases, which are collectively known as synucleinopathies. Growing evidence has supported that the same protein can induce remarkably distinct pathological progresses and disease phenotypes, suggesting the existence of strain difference among α-syn fibrils. Previous studies have shown that α-syn pathology can propagate from the peripheral nervous system (PNS) to the central nervous system (CNS) in a “prion-like” manner. However, the difference of the propagation potency from the periphery to CNS among different α-syn strains remains unknown and the effect of different generation processes of these strains on the potency of seeding and propagation remains to be revealed in more detail.MethodsThree strains of preformed α-syn fibrils (PFFs) were generated in different buffer conditions which varied in pH and ionic concentrations. The α-syn PFFs were intramuscularly (IM) injected into a novel bacterial artificial chromosome (BAC) transgenic mouse line that expresses wild-type human α-syn, and the efficiency of seeding and propagation of these PFFs from the PNS to the CNS was evaluated.ResultsThe three strains of α-syn PFFs triggered distinct propagation patterns. The fibrils generated in mildly acidic buffer led to the most severe α-syn pathology, degeneration of motor neurons and microgliosis in the spinal cord.ConclusionsThe different α-syn conformers generated in different conditions exhibited strain-specific pathology and propagation patterns from the periphery to the CNS, which further supports the view that α-syn strains may be responsible for the heterogeneity of pathological features and disease progresses among synucleinopathies.
Highlights
Accumulation of alpha-synuclein (α-syn) is a main pathological hallmark of Parkinson’s and related diseases, which are collectively known as synucleinopathies
Accumulation of misfolded α-synuclein (α-syn) is associated with a group of neurodegenerative diseases, collectively known as synucleinopathies, including Parkinson’s disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA) and pure autonomic failure [1,2,3,4]. α-Syn aggregates are found in neurons as Lewy bodies (LBs) and Lewy neurites (LNs) in PD and DLB [5, 6]
Characterization of different α-syn fibrils transmission election microscopy (TEM) of α-syn fibrillar polymorphs generated in three different conditions revealed that Strain A generated in buffer A (50 mM Tris, 150 mM KCl, pH 7.5) displayed a cylindrical structure and was short in length (Fig. 1a)
Summary
Accumulation of alpha-synuclein (α-syn) is a main pathological hallmark of Parkinson’s and related diseases, which are collectively known as synucleinopathies. Growing evidence has supported that the same protein can induce remarkably distinct pathological progresses and disease phenotypes, suggesting the existence of strain difference among α-syn fibrils. Synucleinopathies are clinically and pathologically heterogeneous [8], as different regions of the central nervous system (CNS) are affected in distinct diseases [9,10,11,12], suggesting the heterogeneity among distinct α-syn strains. Evidence supporting this is that the pathological α-syn accumulation has been shown in different brain regions in PD patients, following a caudo-rostral pattern [10, 15,16,17]. Embryonic mesencephalic neurons transplanted into the striatum of PD patients developed LB pathology more than 10 years after transplantation, suggesting the host-to-graft LB pathology in the PD patient brains [18,19,20]
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