Investigating the Mechanism of Pathology in Parkinson’s Disease

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Parkinson’s disease (PD) is an age-related neurodegenerative disorder that affects almost 1 million people in the United States. PD is associated with motor symptoms including tremors and stiffness that affect balance and coordination. Symptoms appear as dopaminergic neurons are lost from the midbrain. Neuronal death appears to be due to the accumulation of toxic aggregates, called Lewy bodies, of the protein alpha-synuclein in neurons.

In recent work, Anandhan et al investigated the role of a transcription factor, NRF2, in alpha-synuclein driven pathology. NRF2 is known to regulate the cellular stress response and lack of NRF2 has been shown to exacerbate PD pathology, but the precise roll of NRF2 in alpha-synuclein driven pathology is unknown. The authors created mice that overexpress human alpha-synuclein as a model of PD. They then knocked out the gene coding for NRF2 so study the effect of the loss of NRF2 on behavioral tests, neuron loss in several brain regions, and phosphorylation and oligomerization of alpha-synuclein.

The research compared 4 groups of mice:

  • Expressing human alpha-synuclein, expressing Nrf2 (ha-Syn+/Nrf2+)
  • Expressing human alpha-synuclein, Nrf2 knockout (ha-Syn+/Nrf2-)
  • Not expressing human alpha-synuclein, expressing Nrf2 (ha-Syn-/Nrf2+)
  • Not expressing human alpha-synuclein, Nrf2 knockout (ha-Syn-/Nrf2-)

The study found increased alpha-synuclein phosphorylation and oligomerization in the mice expressing human alpha-synuclein and lacking Nrf2. These mice also lost tyrosine hydroxylase–expressing dopaminergic neurons in the substantia nigra and had behavioral defects consistent with early-state PD. The authors conclude that loss of NRF2 drives development of alpha-synuclein related PD pathogenesis via effects on oxidative stress, proteostasis, inflammation, and cell death. They suggest activating NRF2 might present a way to delay onset or progression of PD.

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