ATG8 proteins are co-factors for human dopaminergic neuronal transcriptional control: implications for neuronal resilience in Parkinson disease

Parkinson disease (PD) is caused by the loss of ventral midbrain dopaminergic neurons (mDANs) in the substantia nigra pars compacta (SNpc). These cells are especially vulnerable to stress but can be protected by autophagy enhancement strategies in vitro and in vivo. In our recent study, we focused on the LIM (Lin11, Isl-1, and Mec-3)-domain homeobox transcription factors LMX1A (LIM homeobox transcription factor 1 alpha) and LMX1B (LIM homeobox transcription factor 1 beta), crucial drivers of mDAN differentiation with roles in autophagy gene expression for stress protection in the developed brain. Using human induced pluripotent stem cell (hiPSC)-derived mDANs and transformed human cell lines, we found that these autophagy gene transcription factors are themselves regulated by autophagy-mediated turnover. LMX1B possesses a non-canonical LC3-interacting region (LIR) in its C-terminus through which it interacts with ATG8 family members. The LMX1B LIR-like domain enables binding to ATG8 proteins in the nucleus, where ATG8 proteins act as co-factors for robust transcription of LMX1B target genes. Thus, we propose a novel role for ATG8 proteins as autophagy gene transcriptional co-factors for mDAN stress protection in PD.