Neuropathologically,
Parkinson’s disease (PD) and dementia
with Lewy bodies (DLB) are characterized by the accumulation of insoluble
aggregates of α-synuclein (α-syn) in the Lewy bodies (LBs).
In addition to full-length α-syn fibrils, C-terminally truncated
α-syn is also abundant in the LBs that acts as seeds and facilitates
the aggregation of the full-length α-syn in vitro and in vivo and induces toxicity. Hence, identifying
molecules that can inhibit the seeding activity of these truncated
forms is of great importance. Here, we report the first in
vitro selection of aptamers targeting the fibrillar forms
of different C-terminally truncated α-syn using systematic evolution
by an exponential enrichment method followed by quantitative high-throughput
DNA sequencing. We identify a panel of aptamers that bound with high
specificity to different truncated forms of α-syn fibrils with
no cross-reactivity toward other amyloid fibrils. Interestingly, two
of the aptamers (named Apt11 and Apt15) show higher affinity to most
C-terminally truncated forms of α-syn fibrils with an evident
inhibition of α-syn-seeded aggregation in vitro by Apt11. This inhibition is further confirmed by circular dichroism,
Congo red binding assay, and electronic microscopy. Moreover, Apt11
is also found to reduce the insoluble phosphorylated form of α-syn
at Ser-129 (pS129-α-syn) in the cell model and also can inhibit
α-syn aggregation using RT-QuIC reactions seeded with brain
homogenates extracted from patients affected by PD. The aptamers discovered
in this study represent potential useful tools for research and diagnostics
or therapy toward PD and DLB.