Pancreatitis and alcoholic pancreatitis are serious health concerns with an urgent need for effective treatment strategies. Alcohol is a known etiological factor for pancreatitis, including acute pancreatitis (AP) and chronic pancreatitis (CP). Excessive alcohol consumption induces many pathological stress responses; of particular note is endoplasmic reticulum (ER) stress and adaptive unfolded protein response (UPR). ER stress results from the accumulation of unfolded/misfolded protein in the ER and is implicated in the pathogenesis of alcoholic pancreatitis. Here, we summarize the possible mechanisms by which ER stress contributes to alcoholic pancreatitis. We also discuss potential approaches targeting ER stress and UPR in developing novel therapeutic strategies for the disease.

Alcohol exposure has detrimental effects on both the developing and mature brain. Endoplasmic reticulum (ER) stress is one of the mechanisms that contributes to alcohol‐induced neuronal damages. Mesencephalic astrocyte‐derived neurotrophic factor (MANF) is an ER stress‐responsive protein and is neuroprotective in multiple neuronal injury and neurodegenerative disease models. MANF deficiency has been shown to exacerbate alcohol‐induced ER stress and neurodegeneration. However, it is unknown whether MANF supplement is sufficient to protect against alcohol neurotoxicity. Alcohol alters MANF expression in the brain, but the mechanisms underlying alcohol modulation of MANF expression remain unclear. This study was designed to determine how alcohol alters MANF expression in neuronal cells and whether exogeneous MANF can alleviate alcohol neurotoxicity. We showed that alcohol increased MANF transcription and secretion without affecting MANF mRNA stability and protein degradation. ER stress was necessary for alcohol‐induced MANF upregulation, as pharmacological inhibition of ER stress by 4‐PBA diminished alcohol‐induced MANF expression. In addition, the presence of ER stress response element II (ERSE‐II) was required for alcohol‐stimulated MANF transcription. Mutations or deletion of this sequence abolished alcohol‐regulated transcriptional activity. We generated MANF knockout (KO) neuronal cells using CRISPR/Cas9. MANF KO cells exhibited increased unfolded protein response (UPR) and were more susceptible to alcohol‐induced cell death. On the other hand, MANF upregulation by the addition of recombinant MANF protein or adenovirus gene transduction protected neuronal cells against alcohol‐induced cell death. Further studies using early postnatal mouse pups demonstrated that enhanced MANF expression in the brain by intracerebroventricular (ICV) injection of MANF adeno‐associated viruses ameliorated alcohol‐induced cell death. Thus, alcohol increased MANF expression through inducing ER stress, which could be a protective response. Exogenous MANF was able to protect against alcohol‐induced neurodegeneration. image

Cerebellar Purkinje cells (PCs) are among the most vulnerable neurons to alcohol neurotoxicity. Alcohol can induce endoplasmic reticulum (ER) stress and alter the structure and function of PCs. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an ER stress inducible protein highly expressed in PCs. It is neuroprotective in various pathological conditions where ER stress is induced. However, it is unknown whether MANF plays a role in protecting PCs from alcohol induced ER stress. In this study, we generated PC-specific MANF knockout (KO) mouse model to test the hypothesis that MANF deficient PCs are more susceptible to binge alcohol exposure induced ER stress and neurodegeneration in the adult brain. We found that PC-specific MANF KO animals show moderate motor function deficit, which was exacerbated by alcohol exposure. Interestingly, female KOs were more sensitive than male KOs to alcohol-induced motor function impairments. In accordance with the behavior changes, alcohol exposure also caused UPR activation, increased intranuclear expression of calcium binding protein Calbindin, and PC degeneration in female but not male MANF KO mice. Spatial transcriptomics and high throughput in situ analyses demonstrated that MANF deficiency altered the transcriptomic landscape in PCs in a sex-specific manner and triggered the expression of genes involved in protein folding and response to ER stress. These results suggests that MANF KO PCs may be predisposed with a higher risk to UPR activation and ER stress in a sex dependent manner, contributing to their vulnerability to alcohol neurotoxicity.

Pancreatitis and alcoholic pancreatitis are serious health concerns, and there is an urgent need for effective treatment strategies. Alcohol is a known etiological factor for pancreatitis, including acute pancreatitis (AP) and chronic pancreatitis (CP). Excessive alcohol consumption induces many pathological stress responses; of particular note is endoplasmic reticulum (ER) stress and adaptive unfolded protein response (UPR). ER stress results from the accumulation of unfolded/misfolded protein in the ER and is implicated in the pathogenesis of alcoholic pancreatitis. Here we summarize the possible mechanisms by which ER stress contributes to alcoholic pancreatitis. We also discuss potential approaches targeting ER stress and UPR for developing novel therapeutic strategies for the disease.

The LRRK2 G2019S mutation is one of the most common genetic risk factors for Parkinson’s disease (PD), yet LRRK2 G2019S knock-in (KI) mice rarely develop robust neurodegeneration under basal conditions, suggesting that additional environmental triggers are required for disease progression. Here, we established a clinically relevant gene–environment interaction mouse model of PD by subjecting LRRK2 G2019S KI mice to recurrent Citrobacter (C.) rodentium infection, a murine model of enteric bacterial inflammation. Repeated infection induced progressive PD-like phenotypes selectively in KI mice, including motor impairment, reduced locomotor activity, impaired motor coordination, selective nigrostriatal dopaminergic neurodegeneration, enhanced neuroinflammation, and pathological phosphorylated α-synuclein (p-αSyn) accumulation, whereas wild-type (WT) mice remained largely resistant. Mechanistically, infected KI mice developed markedly exacerbated colonic inflammation, epithelial barrier dysfunction, increased intestinal permeability, and enhanced inflammasome activation despite normal bacterial clearance, indicating that pathogenic LRRK2 signaling amplifies inflammatory responses rather than impairing antimicrobial defense. In parallel, recurrent infection induced pronounced intestinal p-αSyn accumulation and expansion of pathology beyond the epithelial layer in KI mice, supporting a gut–brain axis mechanism linking intestinal inflammation to neurodegeneration. Collectively, these findings demonstrate that the LRRK2 G2019S mutation functions as a sensitizing factor that cooperates with recurrent enteric inflammation to drive PD-related pathology. This study establishes a physiologically relevant LRRK2 G2019S gene–environment interaction mouse model that recapitulates key behavioral, neuropathological, and inflammatory features of PD.