Abstract Body

Synaptic dysfunction is an early alteration in multiple neurodegenerative disorders including Parkinson’s disease and other synucleinopathies, disorders characterised by the accumulation of α-synuclein (aSyn) in pathological protein inclusions. aSyn is known as a pre-synaptic protein involved in synaptic vesicle trafficking, and SNARE complex formation at the nerve terminals. In pathological conditions, it is associated with alterations of synaptic function. Interestingly, aSyn also occurs in the nucleus where it induces epigenetic changes. RNA-mediated processes contribute to synaptic remodelling by RNA translocation to the synaptic compartment. This is particularly relevant for microRNAs (miRNAs) that can regulate mRNA expression by complementary binding. We are investigating aSyn-mediated epigenetic and epitranscriptomic alterations to uncover the molecular mechanisms underlying alterations in synaptic processes that may contribute to synapse degeneration.

We performed small RNA-Sequencing of the midbrain of 6-month-old transgenic mice expressing A30P mutant αsyn, present in familial forms of PD. Gene ontology (GO) functional annotation and pathway analysis of differentially expressed genes and miRNAs revealed several deregulated biological processes linked with the synaptic compartment.

Our data support the emerging role of specific microRNAs, and RNA modifications, as key regulators of gene expression alterations associated with aSyn. Ultimately, the understanding of the epigenetic and epitranscriptomic alterations in synucleinopathies may lead to the identification of targets for therapeutic intervention and for the development of novel biomarkers.