| 1. |
|
|
| 2. |
- Bakalkin, Georgy, et al.
(författare)
-
Prodynorphin mutations cause the neurodegenerative disorder spinocerebellar ataxia type 23.
- 2010
-
Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 87:5, s. 593-603
-
Tidskriftsartikel (refereegranskat)abstract
- Spinocerebellar ataxias (SCAs) are dominantly inherited neurodegenerative disorders characterized by progressive cerebellar ataxia and dysarthria. We have identified missense mutations in prodynorphin (PDYN) that cause SCA23 in four Dutch families displaying progressive gait and limb ataxia. PDYN is the precursor protein for the opioid neuropeptides, α-neoendorphin, and dynorphins A and B (Dyn A and B). Dynorphins regulate pain processing and modulate the rewarding effects of addictive substances. Three mutations were located in Dyn A, a peptide with both opioid activities and nonopioid neurodegenerative actions. Two of these mutations resulted in excessive generation of Dyn A in a cellular model system. In addition, two of the mutant Dyn A peptides induced toxicity above that of wild-type Dyn A in cultured striatal neurons. The fourth mutation was located in the nonopioid PDYN domain and was associated with altered expression of components of the opioid and glutamate system, as evident from analysis of SCA23 autopsy tissue. Thus, alterations in Dyn A activities and/or impairment of secretory pathways by mutant PDYN may lead to glutamate neurotoxicity, which underlies Purkinje cell degeneration and ataxia. PDYN mutations are identified in a small subset of ataxia families, indicating that SCA23 is an infrequent SCA type (~0.5%) in the Netherlands and suggesting further genetic SCA heterogeneity.
|
|
| 3. |
- Bazov, Igor, et al.
(författare)
-
The endogenous opioid system in human alcoholics : molecular adaptations in brain areas involved in cognitive control of addiction
- 2013
-
Ingår i: Addiction Biology. - : Wiley. - 1355-6215 .- 1369-1600. ; 18:1, s. 161-169
-
Tidskriftsartikel (refereegranskat)abstract
- The endogenous opioid system (EOS) plays a critical role in addictive processes. Molecular dysregulations in this system may be specific for different stages of addiction cycle and neurocircuitries involved and therefore may differentially contribute to the initiation and maintenance of addiction. Here we evaluated whether the EOS is altered in brain areas involved in cognitive control of addiction including the dorsolateral prefrontal cortex (dl-PFC), orbitofrontal cortex (OFC) and hippocampus in human alcohol-dependent subjects. Levels of EOS mRNAs were measured by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and levels of dynorphins by radioimmunoassay (RIA) in post-mortem specimens obtained from 14 alcoholics and 14 controls. Prodynorphin mRNA and dynorphins in dl-PFC, κ-opioid receptor mRNA in OFC and dynorphins in hippocampus were up-regulated in alcoholics. No significant changes in expression of proenkephalin, and µ- and δ-opioid receptors were evident; pro-opiomelanocortin mRNA levels were below the detection limit. Activation of the κ-opioid receptor by up-regulated dynorphins in alcoholics may underlie in part neurocognitive dysfunctions relevant for addiction and disrupted inhibitory control.
|
|
| 4. |
- Enhamre, Erika, et al.
(författare)
-
The expression of growth hormone receptor gene transcript in the prefrontal cortex is affected in male mice with diabetes-induced learning impairments
- 2012
-
Ingår i: Neuroscience Letters. - : Elsevier BV. - 0304-3940 .- 1872-7972. ; 523:1, s. 82-86
-
Tidskriftsartikel (refereegranskat)abstract
- Previous studies have indicated that both growth hormone (GH) deficiency and diabetes are conditions associated with impairments in learning and memory processes. In this study, we investigated the effect of streptozotocin-induced diabetes on spatial learning in mice using the Barnes maze (BM). The expression of the GH receptor (GHR) gene transcript in areas of the brain associated with learning and memory were examined. The results indicated that the GHR gene transcript is up-regulated in the prefrontal cortex (PFC) of diabetic mice compared to controls. In addition, there was a significant correlation between the expression of GHR mRNA and performance in the BM during the acquisition phase in diabetic but not control mice. These results suggest that diabetes induces an imbalance in the GH/IGF-1 system leading to altered activity in the PFC and associated cognitive deficiencies.
|
|
| 5. |
- Hudson, Thomas J., et al.
(författare)
-
International network of cancer genome projects
- 2010
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7291, s. 993-998
-
Tidskriftsartikel (refereegranskat)abstract
- The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.
|
|
| 6. |
- Hussain, Zubair Muhammad, et al.
(författare)
-
Lateralized Response of Dynorphin A Peptide Levels after Traumatic Brain Injury
- 2012
-
Ingår i: Journal of Neurotrauma. - : Mary Ann Liebert Inc. - 0897-7151 .- 1557-9042. ; 29:9, s. 1785-1793
-
Tidskriftsartikel (refereegranskat)abstract
- Traumatic brain injury (TBI) induces a cascade of primary and secondary events resulting in impairment of neuronal networks that eventually determines clinical outcome. The dynorphins, endogenous opioid peptides, have been implicated in secondary injury and neurodegeneration in rodent and human brain. To gain insight into the role of dynorphins in the brain's response to trauma, we analyzed short-term (1-day) and long-term (7-day) changes in dynorphin A (Dyn A) levels in the frontal cortex, hippocampus, and striatum, induced by unilateral left-side or right-side cortical TBI in mice. The effects of TBI were significantly different from those of sham surgery (Sham), while the sham surgery also produced noticeable effects. Both sham and TBI induced short-term changes and long-term changes in all three regions. Two types of responses were generally observed. In the hippocampus, Dyn A levels were predominantly altered ipsilateral to the injury. In the striatum and frontal cortex, injury to the right (R) hemisphere affected Dyn A levels to a greater extent than that seen in the left (L) hemisphere. The R-TBI but not L-TBI produced Dyn A changes in the striatum and frontal cortex at 7 days after injury. Effects of the R-side injury were similar in the two hemispheres. In naive animals, Dyn A was symmetrically distributed between the two hemispheres. Thus, trauma may reveal a lateralization in the mechanism mediating the response of Dyn A-expressing neuronal networks in the brain. These networks may differentially mediate effects of left and right brain injury on lateralized brain functions.
|
|
| 7. |
- Jezierska, Justyna, et al.
(författare)
-
Identification and characterization of novel PDYN mutations in dominant cerebellar ataxia cases.
- 2013
-
Ingår i: Journal of Neurology. - : Springer Science and Business Media LLC. - 0340-5354 .- 1432-1459. ; 260:7, s. 1807-1812
-
Tidskriftsartikel (refereegranskat)abstract
- We have recently identified missense mutations in prodynorphin (PDYN), the precursor to dynorphin opioid peptides, as the cause for spinocerebellar ataxia (SCA23) in Dutch ataxia cases. We report a screen of PDYN for mutations in 371 cerebellar ataxia cases, which had a positive family history; most are of French origin. Sequencing revealed three novel putative missense mutations and one heterozygous two-base pair deletion in four independent SCA patients. These variants were absent in 400 matched controls and are located in the highly conserved dynorphin domain. To resolve the pathogenicity of the heterozygous variants, we assessed the peptide production of the mutant PDYN proteins. Two missense mutations raised dynorphin peptide levels, the two-base pair deletion terminated dynorphin synthesis, and one missense mutation did not affect PDYN processing. Given the outcome of our functional analysis, we may have identified at least two novel PDYN mutations in a French and a Moroccan SCA patient. Our data corroborates recent work that also showed that PDYN mutations only account for a small percentage (~0.1 %) of European SCA cases.
|
|
| 8. |
- Johansson, Erik, et al.
(författare)
-
Exogenous introduction of tissue inhibitor of metalloproteinase 2 reduces accelerated growth of TGF-β-disrupted diffuse-type gastric carcinoma.
- 2010
-
Ingår i: Cancer science. - : Wiley. - 1349-7006 .- 1347-9032. ; 101:11, s. 2398-403
-
Tidskriftsartikel (refereegranskat)abstract
- Diffuse-type gastric carcinoma is characterized by rapid progression and poor prognosis. High expression of transforming growth factor (TGF)-β and thick stromal fibrosis are observed in this type of gastric carcinoma. We have previously shown that disruption of TGF-β signaling via introduction of a dominant negative form of the TGF-β type II receptor (dnTβRII) into diffuse-type gastric cancer cell lines, including OCUM-2MLN, caused accelerated tumor growth through induction of tumor angiogenesis in vivo. In the present study, we show that TGF-β induces upregulation of expression of tissue inhibitor of metalloproteinase 2 (TIMP2) in the OCUM-2MLN cell line in vitro, and that expression of TIMP2 is repressed by dnTβRII expression in vivo. Transplantation of the OCUM-2MLN cells to nude mice exhibited accelerated tumor growth in response to dnTβRII expression, which was completely abolished when TIMP2 was coexpressed with dnTβRII. Although the blood vessel density of TIMP2-expressing tumors was only slightly decreased, the degree of hypoxia in tumor tissues was significantly increased and pericytes covering tumor vasculature were decreased by TIMP2 expression in OCUM-2MLN cells, suggesting that the function of tumor vasculatures was repressed by TIMP2 and consequently tumor growth was reduced. These findings provide evidence that one of the mechanisms of the increase in angiogenesis in diffuse-type gastric carcinoma is the downregulation of the anti-angiogenic protein TIMP2.
|
|
| 9. |
- Sui, Ping, et al.
(författare)
-
Dimethyl-Labeling-Based Protein Quantification and Pathway Search : A Novel Method of Spinal Cord Analysis Applicable for Neurological Studies
- 2013
-
Ingår i: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 12:5, s. 2245-2252
-
Tidskriftsartikel (refereegranskat)abstract
- In this paper we describe a simple, fast, and inexpensive approach for quantitative analysis of proteins originated from small central nervous system (CNS) samples, i.e., rat spinal cord. The presented sample preparation protocol and quantification results from isotope dimethyl labeling were statistically evaluated and approved as a reliable and robust method for animal model studies of neurological disorders. Combined with the biopathway analysis tool IPA, the method was applied for comparative analysis of proteins in the dorsal and ventral segments of the rat spinal cord. The results are in agreement with the previously published protein patterns in these tissues. A majority (73%) of proteins identified as “related with CNS development and functions” were found to be overexpressed in the dorsal section compared to the ventral segment. The pathway related to neuropathic pain was overrepresented in the dorsal tissue samples. The developed novel approach may be applied for analyses of the spinal cord mediated neurological dysfunctions and pathological pain.
|
|
| 10. |
- Sui, Ping, et al.
(författare)
-
Proteomics of Neuropathic Pain : Proteins and Signaling Pathways Affected in a Rat Model
- 2014
-
Ingår i: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 13:9, s. 3957-3965
-
Tidskriftsartikel (refereegranskat)abstract
- The myriad proteins may be involved in the mechanisms underlying the development and maintenance of neuropathic pain, an extremely disabling condition that originates from pathology of the nervous system. To address the mechanisms, we here analyzed proteins and cellular networks in the dorsal spinal cord mediating pain processing in a well-established rat model of neuropathic pain induced by spinal nerve ligation (SNL). Labeling-based proteomic methods together with high-resolution mass spectrometry for proteome analysis were applied. 38 proteins including synapsin 1 and microtubule-associated protein 2 were identified as differently expressed in the SNL group. Pathway analysis suggests that maladaptive changes in the levels of these proteins may contribute to abnormal synaptic transmission and neuronal intracellular signaling underlying the onset and development of neuropathic pain.
|
|
