Novel patented therapeutic approaches targeting the 37/67 kDa laminin receptor for treatment of cancer and Alzheimer’s disease

Jovanović, Katarina; Chetty, Carryn J.; Khumalo, Thandokuhle; Dias, Bianca Da Costa; Ferreira, Eloise; Malindisa, Sibusiso T.; Caveney, R. J.; Letsolo, Boitelo T.; Weiß, Stefan

doi:10.1517/13543776.2015.1014802

Cited by 39 publications

(59 citation statements)

References 102 publications

(80 reference statements)

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“…We mentioned the AS-tDR-011389-Camk2n1 pair in previous text (Gouet et al 2012). Rpsa, a gene found to facilitate the production and internalization of neurotoxic Aβ peptide (Jovanovic et al 2015), was targeted by AS-tDR-013428. AS-tDR-011775 acted on Mobp.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide identification of functional tRNA-derived fragments in Senescence-accelerated mouse prone 8 brain

Zhang

Zheng

et al. 2018

Preprint

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AbstracttRNA-derived fragments (tRFs) have been linked previously to the development of various diseases, such as cancer and viral infection. However, tRFs seem also related to brain aging and related diseases, especially Alzheimer and Parkinson disease. RNA sequencing, a state-of-the-art technology, has allowed for investigation of tRFs in this field. In this study, we investigated the changes of tRFs in the brains of a senescence-accelerated mouse model, senescence-accelerated mouse prone 8 (SAMP8), that show age-dependent deficits in learning and memory; and a control model, senescence-accelerated mouse resistant 1 (SAMR1), with normal aging, both at 7 months of age. A total of 570 tRF transcripts were discovered. Among these transcripts, 8, including 3 upregulated and 5 downregulated transcripts, were differentially expressed in the SAMP8 mice. Then, we obtained 110 potential target genes in a miRNA-like pattern. GO survey implicated these target genes in the function of various aspects, e.g. postsynaptic density (GO: 0014069). Furthermore, we assessed in detail those tRFs whose miRNA-like pattern was most likely to affect the progression of either Alzheimer and Parkinson disease, such as AS-tDR-011775 acting on Mobp and Park2. In fact, we found the tRFs to be involved in the regulation of gene expression by means other than the miRNA-like pattern. Therefore, these 8 dysregulated tRFs may hold consequences far into the future and can be attractive biomarkers and valid targets. In brief, our study is the first to provide a comprehensive analysis on tRFs in SAMP8 mouse brain, and this breakthrough identified promising new targets for preventing the age-related changes of brain and the therapeutic intervention of Alzheimer’s and Parkinson’s.

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Section: Discussionmentioning

confidence: 99%

Genome-wide identification of functional tRNA-derived fragments in Senescence-accelerated mouse prone 8 brain

Zhang

Zheng

et al. 2018

Preprint

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“…169 As a result, cancer has been considered a possible prion-like disease, due to the fibrillogenic behavior of some p53 mutants. 170,171 The "uncontrollable" propagation to supramolecular structures starts with a key slow initiation step, such as the initiation step of the cooperative DS. Ultimately, protein unfolding and folding to a particular form feeds fibrillation and/or amyloidosis.…”

Section: Fibrillization And/or Amyloidosismentioning

confidence: 99%

A review on protein oligomerization process

Liu

2015

Int. J. Precis. Eng. Manuf.

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Enzymes or proteins are commonly present in oligomeric forms for active biological functions. The formation of protein oligomers, either in nature or by artificial means, can take place via covalent bonding or through weak-bond-network associations. Disulfide bonds are more common in forming covalent protein oligomers. Covalent bound protein oligomers usually have additional elements introduced, while proteins associated through weak-bond-networks usually do not involve any additional bound chemical groups. Proteins are commonly present in stable forms or folds. Oligomerization can occur when stable proteins unfold, creating exposed interfaces for association interactions. One well-known process of weak-bond-network oligomerization is domain swapping (DS). Separating the two touching/interacting domains creates opportunities for similar interactions with different protein molecules, leading to oligomerization. Both disulfide bonding and DS oligomerization can be dynamic (or reversible) at least at low Degree of Polymerizations (DPs). The dynamic nature of the protein oligomerization is important for bioactivity control. The morpheein model and the polymorph model are thus important in quantifying enzyme catalyzed biotransformations. Disulfide bonding and DS can act together to form supramolecules. The formation of supramolecules, such as amyloids, in nature can be benign or harmful. Industrial applications of protein oligomerization exploit the special functions /properties of the resultant supramolecules, such as multiple biofunctions, niche structure, etc..

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“…In order to do this, Aβ needs to interact with lipid membranes and cellular receptors [17]. One such receptor is the 37 kDa/ 67 kDa Laminin Receptor Precursor/ High Affinity Laminin Receptor (LRP/LR) [18], also known as LamR1, RPSA and p40 [19]. LRP/LR is a multifunctional receptor mainly found in the lipid raft regions of plasma membranes, as well as in the nucleus [20] and cytoplasm [21].…”

Section: Introductionmentioning

confidence: 99%

LRP::FLAG reduces phosphorylated tau levels in Alzheimer’s Disease

Cuttler

Bignoux

Otgaar

et al. 2020

Preprint

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Alzheimer's disease (AD) is characterized by amyloid beta (Aβ) plaque and neurofibrillary tangle formation, respectively. Neurofibrillary tangles form as a result of the intracellular accumulation of hyperphosphorylated tau. Telomerase activity and levels of the human reverse transcriptase (hTERT) subunit of telomerase are significantly decreased in AD. Recently it has been demonstrated that the 37kDa/67kDa laminin receptor (LRP/LR) interacts with telomerase and is implicated in Aβ pathology. Here we show that LRP/LR co-localizes with tau in the perinuclear cell compartment and FRET confirmed a direct interaction between LRP/LR and tau in HEK-293 cells. Overexpression of LRP::FLAG in HEK-293 and SH-SY5Y cells decreased total and phosphorylated tau levels with a concomitant decrease in PrP c levels, a tauopathy-related protein. Additionally, LRP::FLAG overexpression resulted in increased hTERT levels. These data indicate for the first time a role of LRP/LR in tauopathy of Alzheimer's Disease and recommend LRP::FLAG as a potential alternative therapeutic tool for Alzheimer's Disease treatment through rescuing cells from A induced cytotoxicity and, as shown in this report, decreased phosphorylated tau levels.

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Novel patented therapeutic approaches targeting the 37/67 kDa laminin receptor for treatment of cancer and Alzheimer’s disease

Cited by 39 publications

References 102 publications

Genome-wide identification of functional tRNA-derived fragments in Senescence-accelerated mouse prone 8 brain

Genome-wide identification of functional tRNA-derived fragments in Senescence-accelerated mouse prone 8 brain

A review on protein oligomerization process

LRP::FLAG reduces phosphorylated tau levels in Alzheimer’s Disease

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