N. Tan, G. Roger, P. Gauri, Z. Sara, S. Rahul
Cal Poly Pomona,
United States
Keywords: neurodegeneration, estrogen, Parkinson's disease, endoplasmic reticulum stress, cytisine, dopaminergic neurons
Summary:
Parkinson’s disease (PD) is the second-most common neurodegenerative disorder in the United States. Motor symptoms in PD are caused by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc). However, treatments to reduce SNc DA neuron loss do not exist. In this regard, drugs that reduce hyperactive endoplasmic reticulum (ER) stress, which is known to cause SNc DA neuron loss, can provide an effective treatment for PD. Interestingly, the smoking cessation drug cytisine reduces ER stress, and this is associated with an increase in ER exit sites (ERES) in DA neurons. Therefore, ERES upregulation could play a key role in the ability of cytisine to reduce ER stress and exert neuroprotection. Additionally, cytisine upregulates ERES only in female parkinsonian mice, however, the mechanisms behind this sex-specific ERES upregulation of cytisine are not well understood. We hypothesize that the sex hormone 17-β-estradiol is required for cytisine-mediated ERES upregulation in SNc DA neurons. To test our hypothesis, we performed two methods of 17-β-estradiol depletion in female parkinsonian mice exposed to either saline or cytisine: ovariectomy and administration of the aromatase inhibitor, letrozole. Mice were given a high dose of 6-OHDA to induce neurodegeneration unilaterally. Midbrain sections were immunostained for expression of SEC24D, which is a marker for ERES and tyrosine hydroxylase (TH), which labels SNc DA neurons. All sections were then imaged using confocal microscopy and images were thresholded using the Fiji software. Our preliminary results show that 17-β-estradiol depletion in female parkinsonian mice prevents cytisine-mediated upregulation of ERES. These data suggest that the combination of 17-β-estradiol and cytisine may be necessary for ERES upregulation in SNc DA neurons and therefore may be an effective treatment against Parkinson’s disease in both sexes. Future directions will examine the effects of estrogen depletion on ERES upregulation in SNc DA neurons in female transgenic mice with constitutively upregulated ERES and the effects of estrogen supplementation on ERES upregulation in male mice.