Reduced DJ-1/Nrf2/HO-1 antioxidant signalling is associated with type 2 diabetes-related aggravation of neurodegeneration in a mouse model of Parkinson's disease.

Authors

Honghao Xu, Mengjia Li, Yujia Li, Zhuochi Zou, Zichen Wang, Haroona Bashir, Shu Zhu, Qian Yang, Xianwei Zou

Published in

IBRO neuroscience reports. Volume 21. Pages 324-334. Epub Jul 08, 2026.

Abstract

Parkinson's disease (PD) and type 2 diabetes mellitus (T2DM) are increasingly recognized as comorbid conditions. Epidemiological evidence suggests that T2DM is associated with faster PD progression, but the biological processes that may connect these disorders remain incompletely understood. Oxidative stress is a shared pathological feature of both diseases, and the DJ-1/Nrf2/HO-1 pathway is an important antioxidant defence system.
To determine whether T2DM is associated with more severe PD-like neurodegeneration and whether these changes are accompanied by reduced DJ-1/Nrf2/HO-1 antioxidant signalling in a mouse model of PD-T2DM comorbidity.
Male C57BL/6 mice were assigned to control, T2DM, PD, or PD + T2DM groups. T2DM was induced by high-fat diet feeding combined with streptozotocin injection; PD was induced by unilateral intrastriatal 6-hydroxydopamine injection. Behavioural performance was assessed using rotarod and apomorphine-induced rotation tests. Nigrostriatal pathology was examined by haematoxylin-eosin, Nissl, and tyrosine hydroxylase immunohistochemistry. Oxidative stress markers (SOD, MDA, GSH) and DJ-1/Nrf2/HO-1 protein expression were measured in substantia nigra-striatum and serum. Final analyses included 10 control, 9 T2DM, 9 PD, and 9 PD + T2DM mice, with assay-specific sample sizes indicated in the Methods and figure legends.
Compared with PD mice, PD + T2DM mice exhibited shorter rotarod latency, greater dopaminergic neuron loss, and stronger nigrostriatal oxidative stress (P < 0.05). DJ-1, Nrf2, and HO-1 expression was reduced in the substantia nigra-striatum of disease groups relative to controls, with Nrf2 and HO-1 significantly lower in PD + T2DM than in PD mice. Protein expression correlated positively with rotarod latency and antioxidant indices, and negatively with MDA content and fasting glucose. Serum oxidative stress markers showed similar directional trends, but most between-group differences were not statistically significant.
In this combined toxin- and metabolism-based mouse model, T2DM was associated with more severe PD-like motor impairment and dopaminergic neuron loss, accompanied by reduced DJ-1/Nrf2/HO-1 antioxidant signalling and increased nigrostriatal oxidative stress. These findings are consistent with the possibility that impaired antioxidant defence contributes to PD-T2DM comorbidity, while causal pathway involvement requires confirmation by future gain- or loss-of-function studies.

PMID:
42542636
Bibliographic data and abstract were imported from PubMed on 02 Aug 2026.

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