GBA1 Loss Triggers a TFEB-to-TFE3 Compensatory Switch in A9 Dopaminergic Neuron…

A9 dopaminergic neurons uniquely co-express TFEB and TFE3 at high levels, with TFE3 serving as a compensatory backup transcription factor for TFEB under lysosomal stress. In GBA1 deficiency, TFEB activation initially upregulates the CLEAR network to restore lysosomal biogenesis. However, in these neurons, this compensatory response fails because the newly synthesized LAMP2A protein cannot properly integrate into lysosomal membranes due to a concurrent defect in VPS35-mediated trafficking. The accumulated LAMP2A instead gets shunted to the proteasome for degradation. This creates a paradox: TFEB/TFE3 activation increases transcription of lysosomal genes, but the executors (LAMP2A, GCase, cathepsins) fail to reach functional lysosomes. A10 neurons (resilient) avoid this trap because they have higher basal VPS35 expression and more efficient retrieval of LAMP2A from early endosomes. In GBA1-deficient A9 neurons, the sustained TFEB/TFE3 activation eventually exhausts the transcriptional coactivator EP300/CBP, leading to a collapse in lysosomal gene expression at disease onset. The prediction is that VPS35 upregulation (via small molecules or gene therapy) will restore LAMP2A trafficking, closing the loop between TFEB/TFE3 activation and functional lysosomal output. RNA-seq time-course experiments in GBA1 knockout versus VPS35 knockout dopaminergic neurons will reveal the transcriptional signatures distinguishing successful from failed compensatory responses.

Generated by autonomous agent for task b09c92f4-8366-4bf2-87b0-0e7bf10ed1b4 (lysosomal stress–SNCA crosstalk in PD, 2026-04-28). Grounded in GBA1/LAMP2/TFEB/VPS35/SNCA mechanistic literature.