Cdk5 at crossroads of protein oligomerization in neurodegenerative diseases: facts and hypotheses

Wilkaniec, Anna; Czapski, Grzegorz A.; Adamczyk, Agata

doi:10.1111/jnc.13365

Cited by 54 publications

(38 citation statements)

References 158 publications

(286 reference statements)

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“…We found that injection of Aβ1‐42 monomers was followed by an increase (twofold) of pGSK3β protein levels (Fig. 4A) Then, we tested the levels of CDK5 a protein serine/threonine kinase (Wilkaniec et al ., 2016). As reported in Fig.…”

Section: Resultsmentioning

confidence: 99%

Beta‐amyloid 1‐42 monomers, but not oligomers, produce PHF ‐like conformation of Tau protein

et al. 2016

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SummaryThe mechanistic relationship between amyloid β1‐42 (Aβ1‐42) and the alteration of Tau protein are debated. We investigated the effect of Aβ1‐42 monomers and oligomers on Tau, using mice expressing wild‐type human Tau that do not spontaneously develop Tau pathology. After intraventricular injection of Aβ1‐42, mice were sacrificed after 3 h or 4 days. The short‐lasting treatment with Aβ monomers, but not oligomers, showed a conformational PHF‐like change of Tau, together with hyperphosphorylation. The same treatment induced increase in concentration of GSK3 and MAP kinases. The inhibition of the kinases rescued the Tau changes. Aβ monomers increased the levels of total Tau, through the inhibition of proteasomal degradation. Aβ oligomers reproduced all the aforementioned alterations only after 4 days of treatment. It is known that Aβ1‐42 monomers foster synaptic activity. Our results suggest that Aβ monomers physiologically favor Tau activity and dendritic sprouting, whereas their excess causes Tau pathology. Moreover, our study indicates that anti‐Aβ therapies should be targeted to Aβ1‐42 monomers too.

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Section: Resultsmentioning

confidence: 99%

Beta‐amyloid 1‐42 monomers, but not oligomers, produce PHF ‐like conformation of Tau protein

et al. 2016

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“…Since neurodegenerative diseases share common features and mechanisms responsible for inducing the death of selective neuronal populations [ 49 – 51 ], the extracellular release of ASN as well as activation of P2 receptor may likely contribute, alone or in combination, to these mechanisms and to a neurodegenerative process. Purinergic signaling was previously shown to be involved in the etiopathology of many neurodegenerative disorders [ 52 ].…”

Section: Discussionmentioning

confidence: 99%

P2X7 receptor-pannexin 1 interaction mediates extracellular alpha-synuclein-induced ATP release in neuroblastoma SH-SY5Y cells

Wilkaniec

Gąssowska

Czapski

et al. 2017

Purinergic Signalling

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Abnormalities of alpha-synuclein (ASN), the main component of protein deposits (Lewy bodies), were observed in Parkinson’s disease (PD), dementia with Lewy bodies, Alzheimer’s disease, and other neurodegenerative disorders. These alterations include increase in the levels of soluble ASN oligomers in the extracellular space. Numerous works have identified several mechanisms of their toxicity, including stimulation of the microglial P2X7 receptor leading to oxidative stress. While the significant role of purinergic signaling—particularly, P2 family receptors—in neurodegenerative disorders is well known, the interaction of extracellular soluble ASN with neuronal purinergic receptors is yet to be studied. Therefore, in this study, we have investigated the effect of ASN on P2 purinergic receptors and ATP-dependent signaling. We used neuroblastoma SH-SY5Y cell line and rat synaptoneurosomes treated with exogenous soluble ASN. The experiments were performed using spectrofluorometric, radiochemical, and immunochemical methods. We found the following: (i) ASN-induced intracellular free calcium mobilization in neuronal cells and nerve endings depends on the activation of purinergic P2X7 receptors; (ii) activation of P2X7 receptors leads to pannexin 1 recruitment to form an active complex responsible for ATP release; and (iii) ASN greatly decreases the activity of extracellular ecto-ATPase responsible for ATP degradation. Thus, it is concluded that purinergic receptors might be putative pharmacological targets in the molecular mechanism of extracellular ASN toxicity. Interference with P2X7 signaling seems to be a promising strategy for the prevention or therapy of PD and other neurodegenerative disorders.

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“…Among these genes, there were important transcription factors and kinases associated with AD including LEF1, SOX9, YY1, TCF3, TFDP1, CDK5, CSK and MAP3K3 . Among these genes, overactivation of CDK5 is a major trigger of tau hyperphosphorylation and NFT formation in AD suggesting it may be a target for therapeutic intervention (Wilkaniec et al, 2016). …”

Section: Network-based Approaches Identifies Pathways Specific To Alzmentioning

confidence: 99%

Dissecting the Molecular Mechanisms of Neurodegenerative Diseases through Network Biology

Santiago

Bottero

Potashkin

2017

Front. Aging Neurosci.

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Neurodegenerative diseases are rarely caused by a mutation in a single gene but rather influenced by a combination of genetic, epigenetic and environmental factors. Emerging high-throughput technologies such as RNA sequencing have been instrumental in deciphering the molecular landscape of neurodegenerative diseases, however, the interpretation of such large amounts of data remains a challenge. Network biology has become a powerful platform to integrate multiple omics data to comprehensively explore the molecular networks in the context of health and disease. In this review article, we highlight recent advances in network biology approaches with an emphasis in brain-networks that have provided insights into the molecular mechanisms leading to the most prevalent neurodegenerative diseases including Alzheimer’s (AD), Parkinson’s (PD) and Huntington’s diseases (HD). We discuss how integrative approaches using multi-omics data from different tissues have been valuable for identifying biomarkers and therapeutic targets. In addition, we discuss the challenges the field of network medicine faces toward the translation of network-based findings into clinically actionable tools for personalized medicine applications.

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Cdk5 at crossroads of protein oligomerization in neurodegenerative diseases: facts and hypotheses

Cited by 54 publications

References 158 publications

Beta‐amyloid 1‐42 monomers, but not oligomers, produce PHF ‐like conformation of Tau protein

Beta‐amyloid 1‐42 monomers, but not oligomers, produce PHF ‐like conformation of Tau protein

P2X7 receptor-pannexin 1 interaction mediates extracellular alpha-synuclein-induced ATP release in neuroblastoma SH-SY5Y cells

Dissecting the Molecular Mechanisms of Neurodegenerative Diseases through Network Biology

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