The retrotransposon long interspersed element-1 (L1) occupies nearly 20% of the human genome. Beyond their proven capacity for germline retrotransposition, primate and rodent L1 sequences are expressed and can mobilise in certain somatic cells, including the neuronal lineage. However, the contributions made by L1 to neuronal physiology and neurological disease are largely unknown. In this study, we are investigating L1 activity in substantia nigra (SN) dopaminergic (DA) neurons - a neuronal subset whose selective degeneration constitutes the hallmark of Parkinson's disease (PD). To determine whether L1 contributes to DA neuron vulnerability during neurodegeneration, we have assayed L1 expression in DA neurons under normal and stress-induced conditions in vitro and in vivo.

Our data show that L1 mRNA and proteins are expressed in mouse and human DA neurons. In adult mouse midbrain, L1 mRNA expression is higher in SN compared to ventral tegmental area DA neurons, and this difference is already apparent during midbrain development. Using a common PD experimental model where neurotoxic stress is induced by 6-hydroxydopamine (6-OHDA) injection in the mouse midbrain, we observe significant DA neuron loss without notable differences in L1 mRNA or protein expression. By contrast, when we examine post-mortem human midbrain tissue sections, we find L1 ORF1p expression is lower in the remaining DA neurons from PD patients compared to age-matched controls. To better dissect the association and temporal dynamics of L1 expression and DA neuron toxicity, we established a novel in vitro model of human induced pluripotent stem cell derived-DA (hiPSC-DA) neurons. Exposure to subtoxic levels of 6-OHDA significantly increases ORF1p expression in hiPSC-DA neurons. This could suggest that high L1 expressing-DA neurons are selectively lost during PD progression.

Despite contrasting responses in mouse and human models, L1 expression dynamics throughout disease progression emerge as a potential hallmark of DA neuropathology, warranting further investigation.