ABSTRACT
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the viability of upper and lower motor neurons. Current options for treatment are limited, necessitating deeper understanding of the mechanisms underlying ALS pathogenesis. Glycerophosphodiester phosphodiesterase 2 (GDE2 or GDPD5) is a six-transmembrane protein that acts on the cell surface to cleave the glycosylphosphatidylinositol (GPI)-anchor that tethers some proteins to the membrane. GDE2 is required for the survival of spinal motor neurons but whether GDE2 neuroprotective activity is disrupted in ALS is not known. We utilized a combination of mouse models and patient post-mortem samples to evaluate GDE2 functionality in ALS. Haplogenetic reduction of GDE2 exacerbated motor neuron degeneration and loss in SOD1G93A mice but not in control SOD1WT transgenic animals, indicating that GDE2 neuroprotective function is diminished in the context of SOD1G93A. In tissue samples from patients with ALS, total levels of GDE2 protein were equivalent to healthy controls; however, membrane levels of GDE2 were substantially reduced. Indeed, GDE2 was found to aberrantly accumulate in intracellular compartments of ALS motor cortex, consistent with a disruption of GDE2 function at the cell surface. Supporting the impairment of GDE2 activity in ALS, tandem-mass-tag mass spectrometry revealed a pronounced reduction of GPI-anchored proteins released into the CSF of patients with ALS compared with control patients. Taken together, this study provides cellular and biochemical evidence that GDE2 distribution and activity is disrupted in ALS, supporting the notion that the failure of GDE2-dependent neuroprotective pathways contributes to neurodegeneration and motor neuron loss in disease. These observations highlight the dysregulation of GPI-anchored protein pathways as candidate mediators of disease onset and progression and accordingly, provide new insight into the mechanisms underlying ALS pathogenesis.
Subject(s)
Amyotrophic Lateral Sclerosis , Neurodegenerative Diseases , Amyotrophic Lateral Sclerosis/pathology , Animals , Disease Models, Animal , Humans , Mice , Mice, Transgenic , Motor Neurons/metabolism , Neurodegenerative Diseases/pathology , Spinal Cord/pathology , Superoxide Dismutase/genetics , Superoxide Dismutase/metabolism , Superoxide Dismutase-1/genetics , Superoxide Dismutase-1/metabolismABSTRACT
OBJECTIVE: To compare the impact of the coronavirus disease 2019 (COVID-19) pandemic on the psychological health of patients with infertility who have become pregnant with that of women who have not. DESIGN: Prospective cohort study conducted from April 2020 to June 2020. The participants completed three questionnaires over this period. SETTING: A single large, university-affiliated infertility practice. PATIENTS: A total of 443 pregnant women and 1,476 women still experiencing infertility who completed all three questionnaires. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Patient-reported primary stressor over three months of the first major COVID-19 surge; further data on self-reported sadness, anxiety, loneliness, and the use of personal coping strategies. RESULTS: Pregnant participants were significantly less likely to report taking an antidepressant or anxiolytic medication, were less likely to have a prior diagnosis of depression, were more likely to cite COVID-19 as a top stressor, and overall were less likely to practice stress-relieving activities during the first surge. CONCLUSIONS: Women who became pregnant after receiving treatment for infertility cited the pandemic as their top stressor and were more distressed about the pandemic than their nonpregnant counterparts but were less likely to be engaging in stress-relieving activities. Given the ongoing impact of the pandemic, patients with infertility who become pregnant after receiving treatment should be counseled and encouraged to practice specific stress-reduction strategies.
ABSTRACT
Infertility is a chronic condition commonly accompanied by psychological and emotional distress. A significant contributor to the discontinuation of infertility treatment is the psychological burden of treatment. Many individuals experiencing infertility report high levels of depression and anxiety. Unfortunately, barriers to traditional individual and couples counselling include stigmatization, finances, trepidation, challenges of travel and uncertainty. New technology, such as mobile applications and internet-based programmes, may be a feasible option for reducing the emotional distress of infertility diagnoses and treatments. This review focuses on current and developing technologies designed to decrease emotional distress in individuals with infertility.
