TMBIM6 enhances dopaminergic neuron survival by modulating the IRE1a pathway in Parkinson’s disease

The core pathological hallmark of Parkinson's disease (PD) is the progressive degeneration of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc), driven by misfolding and aggregation of a-synuclein (aSyn) into Lewy bodies. This triggers severe cellular dysfunction, including endoplasmic reticulum (ER) stress and the dysregulation of the unfolded protein response (UPR). TMBIM6, an anti-apoptotic ER protein, inhibits the UPR sensor IRE1a. Although TMBIM6 exhibits neuroprotective effects in neurological disorders, its role in PD-related DAergic neuron survival remains unknown. We report that TMBIM6 mRNA is increased in cellular models exposed to 6-hydroxydopamine (6-OHDA), rotenone, or aSyn preformed fibrils (PFFs), whereas TMBIM6 protein levels are elevated in postmortem PD SNpc, indicating translational relevance. Modulating TMBIM6 expression in DAergic cells and primary neurons showed that knockdown increased aSyn toxicity, while overexpression is protective. Single-cell RNA-seq analysis of PD SN revealed selective disruption of TMBIM6 co-expression with key UPR effectors (HSPA5, ERN1, and XBP1), and reduced TMBIM6 levels in vulnerable DAergic neurons. Mechanistically, TMBIM6 directly binds IRE1a, and aSyn PFFs disrupt this complex, leading to IRE1a activation; genetic or pharmacological IRE1a inhibition prevented cell death in TMBIM6-deficient cells. In vivo, TMBIM6 downregulation in Drosophila melanogaster worsens rotenone-induced DAergic neuron degeneration and motor impairments, while adeno-associated virus (AAV)-mediated TMBIM6 overexpression in mice improves motor function and neuron survival. Our results demonstrate that TMBIM6 modulates ER stress responses, promoting DAergic neuron survival by regulating IRE1a activity. Consequently, the TMBIM6/IRE1a axis represents a promising therapeutic target for mitigating neurodegeneration in PD and related disorders.