Mortalin/GRP75 (glucose regulated protein 75), a member of heat shock protein 70 (Hsp70) family of chaperones, is involved in several cellular processes including proliferation and signaling, and plays a pivotal role in cancer and neurodegenerative disorders.
With a special focus on interacting lipids, here we discuss localization-dependent roles of the membrane-bound Hsp70 in the context of its therapeutic potential, particularly in cancer and neurodegenerative diseases.
These findings demonstrated that Hsp70 was an important modulator in astrocytes induced inflammation, and up-regulation of Hsp70 might be a potential regulating approach for neuroinflammation-related neurodegenerative diseases, such as PD.
In this review, we will discuss the role of intracellular and extracellular STI1 and the Hsp70/Hsp90 chaperone network in mechanisms underlying protein misfolding in neurodegenerative diseases, with particular focus on AD.
Our findings indicate a critical role of HspBP1 in differential CHIP/Hsp70 activities in neuronal and glial cells and the greater neuronal vulnerability to misfolded proteins in neurodegenerative diseases.
Therefore, lower HSP70 expression secondary to oestrogen deficiency increases cardiovascular risk and predisposes the patient to senescence-associated secretory phenotype (SASP) that culminates in chronic inflammatory diseases, such as obesities, type 2 diabetes, neuromuscular and neurodegenerative diseases.
Molecular chaperone Heat Shock Protein 70 (Hsp70) plays an important protective role in various neurodegenerative disorders often associated with aging, but its activity and availability in neuronal tissue decrease with age.
The Hsp70, as a protein stabilizer, has a cellular protection against neurodegeneration of the central nervous system, while Hsp90 promote neurodegenerative disorders indirectly through regulating the expression of Hsp70 and other chaperones.
These studies demonstrate that exogenous Hsp70 may be a practical therapeutic agent for treatment of neurodegenerative diseases associated with abnormal protein biogenesis and cognitive disturbances, such as AD, for which neuroprotective therapy is urgently needed.
The Hsp70 chaperone machinery is an important component of the cellular response towards aggregation prone mutant proteins that are associated with neurodegenerative diseases.
The use of Tat-fusion proteins might therefore be a valuable tool to deliver molecular chaperones like Hsp70 into the brain and may be the starting point for new protective strategies in neurodegenerative diseases.
This novel application of the BiFC assay to the study of the molecular basis of neurodegenerative disorders enabled the direct visualization of alpha-synuclein oligomeric species in living cells and its modulation by Hsp70, constituting a novel important tool in the search for therapeutics for synucleinopathies.
For neurodegenerative disorders associated with protein aggregation, the rationale has been that inhibition of hsp90 by geldanamycin and related compounds activates heat shock factor 1 (HSF1) to induce the production of the chaperones hsp70 and hsp40 that promote disaggregation and protein degradation.
Our studies indicate that HSP70 or related molecular chaperones may provide a means of treating these and other neurodegenerative diseases associated with abnormal protein conformation and toxicity.