Knockdown of Cytosolic Glutaredoxin 1 Leads to Loss of Mitochondrial Membrane Potential: Implication in Neurodegenerative Diseases

Mitochondrial dysfunction including that caused by oxidative stress has been implicated in the pathogenesis of neurodegenerative diseases. Glutaredoxin 1 (Grx1), a cytosolic thiol disulfide oxido-reductase, reduces glutathionylated proteins to protein thiols and helps maintain redox status of proteins during oxidative stress. Grx1 downregulation aggravates mitochondrial dysfunction in animal models of neurodegenerative diseases, such as Parkinson's and motor neuron disease. We examined the mechanism underlying the regulation of mitochondrial function by Grx1. Downregulation of Grx1 by shRNA results in loss of mitochondrial membrane potential (MMP), which is prevented by the thiol antioxidant, α-lipoic acid, or by cyclosporine A, an inhibitor of mitochondrial permeability transition. The thiol groups of voltage dependent anion channel (VDAC), an outer membrane protein in mitochondria but not adenosine nucleotide translocase (ANT), an inner membrane protein, are oxidized when Grx1 is downregulated. We then examined the effect of β-N-oxalyl amino-L-alanine (L-BOAA), an excitatory amino acid implicated in neurolathyrism (a type of motor neuron disease), that causes mitochondrial dysfunction. Exposure of cells to L-BOAA resulted in loss of MMP, which was prevented by overexpression of Grx1. Grx1 expression is regulated by estrogen in the CNS and treatment of SH-SY5Y cells with estrogen upregulated Grx1 and protected from L-BOAA mediated MMP loss. Our studies demonstrate that Grx1, a cytosolic oxido-reductase, helps maintain mitochondrial integrity and prevents MMP loss caused by oxidative insult. Further, downregulation of Grx1 leads to mitochondrial dysfunction through oxidative modification of the outer membrane protein, VDAC, providing support for the critical role of Grx1 in maintenance of MMP

A Role for Thrombospondin-1 Deficits in Astrocyte-Mediated Spine and Synaptic Pathology in Down's Syndrome

Down's syndrome (DS) is the most common genetic cause of mental retardation. Reduced number and aberrant architecture of dendritic spines are common features of DS neuropathology. However, the mechanisms involved in DS spine alterations are not known. In addition to a relevant role in synapse formation and maintenance, astrocytes can regulate spine dynamics by releasing soluble factors or by physical contact with neurons. We have previously shown impaired mitochondrial function in DS astrocytes leading to metabolic alterations in protein processing and secretion. In this study, we investigated whether deficits in astrocyte function contribute to DS spine pathology.Using a human astrocyte/rat hippocampal neuron coculture, we found that DS astrocytes are directly involved in the development of spine malformations and reduced synaptic density. We also show that thrombospondin 1 (TSP-1), an astrocyte-secreted protein, possesses a potent modulatory effect on spine number and morphology, and that both DS brains and DS astrocytes exhibit marked deficits in TSP-1 protein expression. Depletion of TSP-1 from normal astrocytes resulted in dramatic changes in spine morphology, while restoration of TSP-1 levels prevented DS astrocyte-mediated spine and synaptic alterations. Astrocyte cultures derived from TSP-1 KO mice exhibited similar deficits to support spine formation and structure than DS astrocytes.These results indicate that human astrocytes promote spine and synapse formation, identify astrocyte dysfunction as a significant factor of spine and synaptic pathology in the DS brain, and provide a mechanistic rationale for the exploration of TSP-1-based therapies to treat spine and synaptic pathology in DS and other neurological conditions

Prospective cohort study of body mass index and the risk of hospitalisation: findings from 246361 participants in the 45 and Up Study

Objective To quantify the risk of hospital admission in relation to fine increments in body mass index (BMI). Design, setting and participants Population-based prospective cohort study of 246 361 individuals aged ≥45 years, from New South Wales, Australia, recruited from 2006-2009. Self-reported data on BMI and potential confounding/mediating factors were linked to hospital admission and death data. Main outcomes Cox-models were used to estimate the relative risk (RR) of incident all-cause and diagnosis-specific hospital admission (excluding same day) in relation to BMI. Results There were 61 583 incident hospitalisations over 479 769 person-years (py) of observation. In men, hospitalisation rates were lowest for BMI 20–-2 (age-standardised rate:120/1000 py) and in women for BMI 18.5– -2 (102/1000 py); above these levels, rates increased steadily with increasing BMI; rates were 203 and 183/1000 py, for men and women with BMI 35-50 kg m -2, respectively. This pattern was observed regardless of baseline health status, smoking status and physical activity levels. After adjustment, the RRs (95% confidence interval) per 1 kg m -2 increase in BMI from ≥20 kg m -2 were 1.04(1.03-1.04) for men and 1.04(1.04-1.05) for women aged 45-64; corresponding RRs for ages 65-79 were 1.03(1.02-1.03) and 1.03(1.03-1.04); and for ages ≥80 years, 1.01(1.00-1.01) and 1.01(1.01-1.02). Hospitalisation risks were elevated for a large range of diagnoses, including a number of circulatory, digestive, musculoskeletal and respiratory diseases, while being protective for just two-fracture and hernia. Conclusions Above normal BMI, the RR of hospitalisation increases with even small increases in BMI, less so in the elderly. Even a small downward shift in BMI, among those who are overweight not just those who are obese, could result in a substantial reduction in the risk of hospitalisation