CTNS
Cystinosin
Publications[править]
Aging is associated with a gradual decline of cellular proteostasis, giving rise to devastating protein misfolding diseases, such as Alzheimer disease (AD) or Parkinson disease (PD). These diseases often exhibit a complex pathology involving non-cell autonomous proteotoxic effects, which are still poorly understood. Using [i]Caenorhabditis elegans[/i] we investigated how local protein misfolding is affecting neighboring cells and tissues showing that misfolded PD-associated SNCA/α-synuclein is accumulating in highly dynamic endo-lysosomal vesicles. Irrespective of whether being expressed in muscle cells or dopaminergic neurons, accumulated proteins were transmitted into the hypodermis with increasing age, indicating that epithelial cells might play a role in remote degradation when the local endo-lysosomal degradation capacity is overloaded. Cell biological and genetic approaches revealed that inter-tissue dissemination of SNCA was regulated by endo- and exocytosis (neuron/muscle to hypodermis) and basement membrane remodeling (muscle to hypodermis). Transferred SNCA conformers were, however, inefficiently cleared and induced endo-lysosomal membrane permeabilization. Remarkably, reducing INS (insulin)-IGF1 (insulin-like growth factor 1) signaling provided protection by maintaining endo-lysosomal integrity. This study suggests that the degradation of lysosomal substrates is coordinated across different tissues in metazoan organisms. Because the chronic dissemination of poorly degradable disease proteins into neighboring tissues exerts a non-cell autonomous toxicity, this implies that restoring endo-lysosomal function not only in cells with pathological inclusions, but also in apparently unaffected cell types might help to halt disease progression. : AD: Alzheimer disease; BM: basement membrane; BWM: body wall muscle; CEP: cephalic sensilla; CLEM: correlative light and electron microscopy; CTNS-1: cystinosin (lysosomal protein) homolog; DA: dopaminergic; DAF-2: abnormal dauer formation; ECM: extracellular matrix; FLIM: fluorescence lifetime imaging microscopy; fps: frames per second; GFP: green fluorescent protein; HPF: high pressure freezing; IGF1: insulin-like growth factor 1; INS: insulin; KD: knockdown; LMP: lysosomal membrane permeabilization; MVB: multivesicular body; NOC: nocodazole; PD: Parkinson disease; RFP: red fluorescent protein; RNAi: RNA interference; sfGFP: superfolder GFP; SNCA: synuclein alpha; TEM: transmission electron microscopy; TNTs: tunneling nanotubes; TCSPC: time correlated single photon counting; YFP: yellow fluorescent protein.
Keywords
- Alpha-synuclein
- aging
- intercellular spreading
- lysosomal homeostasis
- lysosomal membrane permeabilization
- neurodegenerative diseases
- non-cell autonomous toxicity
- proteostasis
The use of multivitamin-mineral supplements has become increasingly common, but whether the use of such supplements improves micronutrient status remains still unclear. The objective of this report is to investigate how a long-term vitamin-mineral supplementation following the US Recommended Daily Intake (RDI) affected the plasma levels of selected nutrients in a subset (No. = 407) of participants in the Italian-American Clinical Trial of Nutritional Supplements and Age-related Cataract (CTNS). The CTNS was a double-blind, single centre, controlled clinical trial of 1020 participants aged 55-75 years randomized to a daily tablet of Centrum(R) or placebo. A representative sample of 40% of the 1020 subjects, whom plasma level of selected vitamins was determined at the baseline, was retested throughout the treatment period that averaged 9.0 /- 2.4 years. Participants assigned to Centrum(R) showed a significant increase (p < 0.005) in mean/median plasma levels of vitamin E, beta-carotene, folate, and vitamin B12, and an improved riboflavin status when compared with participants assigned to placebo. Differences concerning vitamin C were statistically less relevant and those concerning vitamin A were at a borderline level. In the treated group the effect of supplementation on plasma levels of vitamins A, E, and C, and on the glutathione reductase activation coefficient was significantly higher in participants with lower nutritional status at baseline.
MeSH Terms
- Aged
- Aging
- Cataract
- Dietary Supplements
- Drug Combinations
- Female
- Follow-Up Studies
- Humans
- Italy
- Male
- Middle Aged
- Minerals
- United States
- Vitamins
Cystinosis is a lysosomal storage disorder characterised by progressive cystine accumulation. The causative gene, CTNS, encodes cystinosin, the lysosomal cystine transporter. Neurological deterioration is one of the last symptoms to appear and the least well characterised. Visuospatial memory deficits have been documented in patients. To determine whether the cystinosis mouse model presents similar anomalies, we studied the learning and memory abilities of young and middle-aged Ctns(-/-) mice. We did not detect deficits in young Ctns(-/-) mice. In contrast, spatial reference and working memory deficits were detected in middle-aged Ctns(-/-) mice. Elevated cystine levels were detected in the hippocampus, cerebellum, forebrain and brainstem of all Ctns(-/-) mice, which increased with age and were consistent with the appearance of impairments. Our results strongly suggest that the cystinosis-associated CNS anomalies are due to progressive cystine accumulation. Furthermore, the Ctns(-/-) mice serve as a model to investigate the evolution of these anomalies and test the efficiency of existing and novel treatments to cross the blood-brain barrier and reduce lysosomal cystine levels.
MeSH Terms
- Aging
- Animals
- Brain
- Cystine
- Memory
- Memory Disorders
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Tissue Distribution
To investigate the association at baseline between plasma levels of selected vitamins and the presence and type of cataract in the participants in The Italian-American Trial of Nutritional Supplements and Age-related Cataract. At baseline, the participants (1020, 710 with "early cataract" and 310 with "no cataract," 55-75 years of age) received an ocular examination, photographic lens grading, and measurement of plasma levels of vitamins A, C, E, beta-carotene, and of red blood cell glutathione reductase activity. In multiple logistic models adjusted for potential confounders, high vitamin C levels were associated with a protective effect on nuclear (N) [OR: 0.54; 95% CI: 0.30, 0.97] and posterior subcapsular (PSC) cataract (OR: 0.37; 95% CI: 0.15, 0.93). High vitamin E levels were associated with increased prevalence of cortical cataract (C) (OR: 1.99; 95% CI: 1.02-3.90), PSC (OR: 3.27; 95% CI: 1.34, 7.96) and of any cataract (OR: 1.86; 95% CI: 1.08, 3.18). In agreement with some earlier studies, we found higher plasma levels of vitamin C to be associated with reduced prevalence of N and PSC cataracts. The finding of an increased prevalence of some types of cataract with higher levels of vitamin E was unexpected, has not been previously reported, and could be due to unadjusted confounding.
MeSH Terms
- Aged
- Aging
- Ascorbic Acid
- Cataract
- Chromatography, High Pressure Liquid
- Dietary Supplements
- Erythrocyte Membrane
- Female
- Glutathione Reductase
- Humans
- Italy
- Male
- Middle Aged
- Prevalence
- Quality Control
- United States
- Vitamin A
- Vitamin E
- beta Carotene