Heat shock protein 90: translation from cancer to Alzheimer's disease treatment?

Both malignant transformation and neurodegeneration, as it occurs in Alzheimer's disease, are complex and lengthy multistep processes characterized by abnormal expression, post-translational modification, and processing of certain proteins. To maintain and allow the accumulation of these dysregulated processes, and to facilitate the step-wise evolution of the disease phenotype, cells must co-opt a compensatory regulatory mechanism. In cancer, this role has been attributed to heat shock protein 90 (Hsp90), a molecular chaperone that maintains the functional conformation of multiple proteins involved in cell-specific oncogenic processes. In this sense, at the phenotypic level, Hsp90 appears to serve as a biochemical buffer for the numerous cancer-specific lesions that are characteristic of diverse tumors. The current review proposes a similar role for Hsp90 in neurodegeneration. It will present experimentally demonstrated, but also hypothetical, roles that suggest Hsp90 can act as a regulator of pathogenic changes that lead to the neurodegenerative phenotype in Alzheimer's disease

Heat shock protein 90 in neurodegenerative diseases

Hsp90 is a molecular chaperone with important roles in regulating pathogenic transformation. In addition to its well-characterized functions in malignancy, recent evidence from several laboratories suggests a role for Hsp90 in maintaining the functional stability of neuronal proteins of aberrant capacity, whether mutated or over-activated, allowing and sustaining the accumulation of toxic aggregates. In addition, Hsp90 regulates the activity of the transcription factor heat shock factor-1 (HSF-1), the master regulator of the heat shock response, mechanism that cells use for protection when exposed to conditions of stress. These biological functions therefore propose Hsp90 inhibition as a dual therapeutic modality in neurodegenerative diseases. First, by suppressing aberrant neuronal activity, Hsp90 inhibitors may ameliorate protein aggregation and its associated toxicity. Second, by activation of HSF-1 and the subsequent induction of heat shock proteins, such as Hsp70, Hsp90 inhibitors may redirect neuronal aggregate formation, and protect against protein toxicity. This mini-review will summarize our current knowledge on Hsp90 in neurodegeneration and will focus on the potential beneficial application of Hsp90 inhibitors in neurodegenerative diseases

Phosphorylation of p125FAK and paxillin focal adhesion proteins in src-transformed cells with different metastatic capacity

AbstractHamster fibroblasts transformed by Rous sarcoma virus (RSV) display different metastatic potentials that are associated with specific structural features of the v-src oncoprotein. This diverse metastatic activity could be due to various tyrosine phosphorylation levels of specific src protein substrates. To check this hypothesis, phosphorylation of the FAK and paxillin proteins, involved in signal transduction pathways and known as src protein substrates, was tested. It was shown that FAK and paxillin are hyperphosphorylated in the high metastatic cell lines as compared with the phosphotyrosine level of these proteins found in the low metastatic cell lines. In addition, our data confirm that v-src protein plays a direct role in paxillin phosphorylation

Surface spin magnetism controls the polarized exciton emission from CdSe nanoplatelets

The surface of nominally diamagnetic colloidal CdSe nanoplatelets can demonstrate paramagnetism owing to the uncompensated spins of dangling bonds (DBSs). We reveal that by optical spectroscopy in high magnetic fields up to 15 Tesla using the exciton spin as probe of the surface magnetism. The strongly nonlinear magnetic field dependence of the circular polarization of the exciton emission is determined by the DBS and exciton spin polarization as well as by the spin-dependent recombination of dark excitons. The sign of the exciton-DBS exchange interaction can be adjusted by the nanoplatelet growth conditions

Electron and hole g-factors and spin dynamics of negatively charged excitons in CdSe/CdS colloidal nanoplatelets with thick shells

We address spin properties and spin dynamics of carriers and charged excitons in CdSe/CdS colloidal nanoplatelets with thick shells. Magneto-optical studies are performed by time-resolved and polarization-resolved photoluminescence, spin-flip Raman scattering and picosecond pump-probe Faraday rotation in magnetic fields up to 30 T. We show that at low temperatures the nanoplatelets are negatively charged so that their photoluminescence is dominated by radiative recombination of negatively charged excitons (trions). Electron g-factor of 1.68 is measured and heavy-hole g-factor varying with increasing magnetic field from -0.4 to -0.7 is evaluated. Hole g-factors for two-dimensional structures are calculated for various hole confining potentials for cubic- and wurtzite lattice in CdSe core. These calculations are extended for various quantum dots and nanoplatelets based on II-VI semiconductors. We developed a magneto-optical technique for the quantitative evaluation of the nanoplatelets orientation in ensemble

Addressing the exciton fine structure in colloidal nanocrystals: the case of CdSe nanoplatelets

We study the band-edge exciton fine structure and in particular its bright-dark splitting in colloidal semiconductor nanocrystals by four different optical methods based on fluorescence line narrowing and time-resolved measurements at various temperatures down to 2 K. We demonstrate that all these methods provide consistent splitting values and discuss their advances and limitations. Colloidal CdSe nanoplatelets with thicknesses of 3, 4 and 5 monolayers are chosen for experimental demonstrations. The bright-dark splitting of excitons varies from 3.2 to 6.0 meV and is inversely proportional to the nanoplatelet thickness. Good agreement between experimental and theoretically calculated size dependence of the bright-dark exciton slitting is achieved. The recombination rates of the bright and dark excitons and the bright to dark relaxation rate are measured by time-resolved techniques

Dynamics of Intraband and Interband Auger Processes in Colloidal Core-Shell Quantum Dots.

Conventional colloidal quantum dots (QDs) suffer from rapid energy losses by nonradiative (Auger) processes, leading to sub-ns lifetimes in all excited states but the lowest-energy single exciton. Suppression of interband Auger decay, such as biexciton Auger recombination, has been achieved with the design of heterostructured core-shell QDs. Auger-like processes are also believed to be responsible for rapid intraband hot-electron cooling in QDs. However, the simultaneous effect of shell growth on interband Auger recombination and intraband hot-electron cooling has not been addressed. Here we investigate how the growth of a CdS shell affects these two relaxation processes in CdSe/CdS core-shell QDs. Using a combination of ultrafast pump-push-probe spectroscopy on the QD ensemble and analysis of the photon statistics from single QDs, we find that Auger losses in the biexciton state are suppressed with increasing shell thickness, while hot-electron cooling remains unaffected. Calculations conducted within an eight-band k·p model confirm the experimental dependence of the biexciton Auger decay on the shell thickness, and provide insights into the factors determining the cooling rate of hot carriers.This work is part of the research program of the ”Stichting voor Fundamenteel Onderzoek der Materie (FOM)”, which is financially supported by the ”Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO)”. A.L.E. acknowledges the financial support of the Office of Naval Research (ONR) through the Naval Research Laboratory Basic Research Program.This is the author accepted manuscript. The final version is available from ACS via http://dx.doi.org/10.1021/acsnano.5b0449