RAN
GTP-binding nuclear protein Ran (Androgen receptor-associated protein 24) (GTPase Ran) (Ras-like protein TC4) (Ras-related nuclear protein) [ARA24] [OK/SW-cl.81]
Publications[править]
Rapid Automatized Naming (RAN), a task in which participants must name a series of items as rapidly as possible, has been very useful as a measure of cognitive abilities that predict reading skill both in children and in young adults (YAs). This study examined RAN performance of 100 YAs and 80 cognitively healthy older adults (OAs). RAN performance was highly reliable but showed only a few weak correlations to other measures of individual differences used to study cognitive aging. RAN performance did not differ significantly by age group for symbolic RANs but was significantly slower for OAs than YAs for non-symbolic RANs. This pattern suggests that healthy aging is associated with little to no decline in the ability to sustain overlapping encoding and production of a sequence of items when it involves the form-to-form mapping required by symbolic RANs but with measurable decline in that ability when it involves the concept-to-form mapping required by non-symbolic RANs.
Keywords
- Aging
- RAN
- individual differences
- naming
- reading
The AMP-activated protein kinase (AMPK) regulates cellular energy homeostasis by sensing the metabolic status of the cell. AMPK is regulated by phosphorylation and dephosphorylation as a result of changing AMP/ATP levels and by removal of inhibitory ubiquitin residues by USP10. In this context, we identified the GID-complex, an evolutionarily conserved ubiquitin-ligase-complex (E3), as a negative regulator of AMPK activity. Our data show that the GID-complex targets AMPK for ubiquitination thereby altering its activity. Cells depleted of GID-subunits mimic a state of starvation as shown by increased AMPK activity and macroautophagic/autophagic flux as well as reduced MTOR activation. Consistently, [i]gid[/i]-genes knockdown in [i]C. elegans[/i] results in increased organismal lifespan. This study may contribute to understand metabolic disorders such as type 2 diabetes mellitus and morbid obesity and implements alternative therapeutic approaches to alter AMPK activity. ACTB: actin, beta; ADP: adenosine diphosphate; AMP: adenosine monophosphate; AMPK: AMP-activated protein kinase; ARMC8: armadillo repeat containing 8; ATP: adenosine triphosphate; BafA1: bafilomycin A ; BCAA: branched chain amino acid; BICC1: BicC family RNA binding protein 1; BSA: bovine serum albumin; CAMKK2 kinase: calcium/calmodulin dependent protein kinase kinase 2, beta; CHX: cycloheximide; DMEM: Dulbecco's modified Eagle's medium; E1: ubiquitin-activating enzyme; E2: ubiquitin-conjugating enzyme; E3: ubiquitin ligase; ECAR: extracellular acidification rate; FACS: fluorescent associated cell sorter; FBP1: fructose-bisphosphatase 1; FCCP: carbonyl cyanide-4 (trifluoromethoxy) phenylhydrazone; G6P: glucose-6-phosphate; GDP: guanosine diphosphate; GFP: green fluorescent protein; GID: glucose induced degradation deficient; GMP: guanosine monophosphate; GTP: guanosine triphosphate; HBP1: high mobility group box transcription factor 1; HPRT: hypoxanthine guanine phosphoribosyl transferase; KO: knock out; LE: long exposure; MAEA: macrophage erythroblast attacher; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MKLN1: muskelin 1; mRNA: messenger RNA; MTOR: mechanistic target of rapamycin; NES: normalized enrichment score; OCR: oxygen consumption rate; PBS: phosphate buffered saline; PCK1: phosphoenolpyruvate carboxykinase 1, cytosolic; PCR: polymerase chain reaction; PFA: paraformaldehyde; RANBP9: RAN binding protein 9; RING: really interesting new gene; RMND5: required for meiotic nuclear division5 homolog; RPS6: ribosomal protein S6; RPTOR: regulatory associated protein of MTOR, complex 1; SE: short exposure; SEM: standard error of the mean; SQSTM1/p62: sequestosome 1; TSC2: tuberous sclerosis complex 2; TUBA4A: tubulin; TUBE: tandem ubiquitin binding entities; Ub: ubiquitin; UPS: ubiquitin proteasome system; WDR26: WD repeat domain 26; WT: wild type.
Keywords
- AMPK
- GID
- autophagy
- longevity
- primary cilium
- ubiquitination
Spinocerebellar ataxia type 8 (SCA8) is caused by a bidirectionally transcribed CTG·CAG expansion that results in the [i]in vivo[/i] accumulation of CUG RNA foci, an ATG-initiated polyGln and a polyAla protein expressed by repeat-associated non-ATG (RAN) translation. Although RAN proteins have been reported in a growing number of diseases, the mechanisms and role of RAN translation in disease are poorly understood. We report a novel toxic SCA8 polySer protein which accumulates in white matter (WM) regions as aggregates that increase with age and disease severity. WM regions with polySer aggregates show demyelination and axonal degeneration in SCA8 human and mouse brains. Additionally, knockdown of the eukaryotic translation initiation factor eIF3F in cells reduces steady-state levels of SCA8 polySer and other RAN proteins. Taken together, these data show polySer and WM abnormalities contribute to SCA8 and identify eIF3F as a novel modulator of RAN protein accumulation.
MeSH Terms
- Aging
- Animals
- Eukaryotic Initiation Factor-3
- HeLa Cells
- Humans
- Mice
- Mice, Transgenic
- Nerve Tissue Proteins
- Spinocerebellar Degenerations
- White Matter
Keywords
- RAN translation
- eIF3F
- polyserine
- spinocerebellar ataxia type 8 (SCA8)
- white matter
Human aging studies suggest that an increased use of top-down knowledge-based resources would compensate for degraded upstream acoustic information to accurately identify important temporally rich signals. Sinusoidal amplitude-modulated (SAM) stimuli have been used to mimic the fast-changing temporal features in speech and species-specific vocalizations. Single units were recorded from auditory thalamus [medial geniculate body (MGB)] of young awake, aged awake, young anesthetized, and aged anesthetized rats. SAM stimuli were modulated between 2 and 1024 Hz with the modulation frequency (fm) changed randomly (RAN) across trials or sequentially (SEQ) after several repeated trials. Units were found to be RAN-preferring, SEQ-preferring, or nonselective based on total firing rate. Significant anesthesia and age effects were found. The majority (86%) of young anesthetized units preferred RAN SAM stimuli; significantly fewer young awake units (51%, p < 0.0001) preferred RAN SAM signals with 16% preferring SEQ SAM. Compared with young awake units, there was a significant increase of aged awake units preferring SEQ SAM (30%, p < 0.05). We examined RAN versus SEQ differences across fms by measuring selective fm areas under the rate modulation transfer function curve. The largest age-related differences from awake animals were found for mid-to-high fms in MGB units, with young units preferring RAN SAM while aged units showed a greater preference for SEQ-presented SAM. Together, these findings suggest that aged MGB units/animals employ increased top-down mediated stimulus context to enhance processing of "expected" temporally rich stimuli, especially at more challenging higher fms. Older individuals compensate for impaired ascending acoustic information by increasing use of cortical cognitive and attentional resources. The interplay between ascending and descending influences in the thalamus may serve to enhance the salience of speech signals that are degraded as they ascend to the cortex. The present findings demonstrate that medial geniculate body units from awake rats show an age-related preference for predictable modulated signals relative to randomly presented signals, especially at higher, more challenging modulation frequencies. Conversely, units from anesthetized animals, with little top-down influences, strongly preferred randomly presented modulated sequences. These results suggest a neuronal substrate for an age-related increase in experience/attentional-based influences in processing temporally complex auditory information in the auditory thalamus.
MeSH Terms
- Acoustic Stimulation
- Anesthesia
- Anesthetics, Intravenous
- Animals
- Attention
- Auditory Pathways
- Evoked Potentials, Auditory, Brain Stem
- Male
- Neurons
- Rats
- Rats, Inbred F344
- Thalamus
- Urethane
Keywords
- SAM sequence detection
- aging
- anesthesia
- awake
- thalamus