Abstract
Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a central regulator of cellular stress responses and its transcriptional activation promotes multiple cellular defense and survival mechanisms. The loss of NRF2 has been shown to increase oxidative and proteotoxic stress, two key pathological features of neurodegenerative disorders such as Parkinson’s disease (PD). Moreover, compromised redox homeostasis and protein quality control can cause the accumulation of pathogenic proteins, including alpha-synuclein (α-Syn) which plays a key role in PD. However, despite this link, the precise mechanisms by which NRF2 may regulate PD pathology is not clear. In this study, we generated a humanized mouse model to study the importance of NRF2 in the context of α-Syn-driven neuropathology in PD. Specifically, we developed NRF2 knockout and wild-type mice that overexpress human α-Syn (hα-Syn+/Nrf2-/- and hα-Syn+/Nrf2+/+ respectively) and tested changes in their behavior through nest building, challenging beam, and open field tests at three months of age. Cellular and molecular alterations in α-Syn, including phosphorylation and subsequent oligomerization, as well as changes in oxidative stress, inflammation, and autophagy were also assessed across multiple brain regions. It was observed that although monomeric α-Syn levels did not change, compared to their wild-type counterparts, hα-Syn+/Nrf2-/- mice exhibited increased phosphorylation and oligomerization of α-Syn. This was associated with a loss of tyrosine hydroxylase expressing dopaminergic neurons in the substantia nigra, and more pronounced behavioral deficits reminiscent of early-stage PD, in the hα-Syn+/Nrf2-/- mice. Furthermore, hα-Syn+/Nrf2-/- mice showed significantly amplified oxidative stress, greater expression of inflammatory markers, and signs of increased autophagic burden, especially in the midbrain, striatum and cortical brain regions. These results support an important role for NRF2, early in PD progression. More broadly, it indicates NRF2 biology as fundamental to PD pathogenesis and suggests that targeting NRF2 activation may delay the onset and progression of PD.
Highlights
Nuclear factor-like 2 is a transcription factor that is critical to the cell’s homeostatic mechanism and functions to promote a broad range of cell survival processes in response to stress [1,2,3]
The hα-Syn+/Nrf2+/- mice were further bred over a few generations to obtain four genotypes: (1) hα-Syn+ with both endogenous copies of Nrf2, (2) hα-Syn+ lacking both copies of Nrf2, (3) wild-type mice with both copies of Nrf2, and (4) wild-type mice lacking both copies of Nrf2 (Fig. 1A)
The genotypes of all four strains were determined before the experiment with polymerase chain reaction (PCR) amplification analysis of DNA obtained from tail tissue (Fig. 1B, C), and western blot analysis (Fig. 1D)
Summary
Nuclear factor (erythroid-derived 2)-like 2 (or NRF2) is a transcription factor that is critical to the cell’s homeostatic mechanism and functions to promote a broad range of cell survival processes in response to stress [1,2,3]. In its native form α-Syn has diverse neural functions, when misfolded, it forms intracellular inclusions within the cell body (Lewy bodies) and processes (Lewy neurites) which cause cellular toxicity [15, 16] This abnormal α-Syn accumulation is associated with changes such as oxidative stress, inflammation and altered proteostasis, which are other key aspects of PD [17,18,19,20,21]. We found that NRF2 loss significantly worsens sensorimotor function, increases α-Syn aggregation, oxidative stress, inflammation, and autophagic burden, and induces DA neuron degeneration, as early as 3 mos of age To our knowledge, these data are the first to explicate NRF2’s involvement in promoting α-Syn pathology and its functional effects in a translationally relevant representation of PD onset and progression
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
