Antibodies to mycobacterial 65 kDa and 70 kDa heat shock proteins in neurodegenerative diseases

The intra- and extracellular accumulation of misfolded and aggregated amyloid proteins is a common feature in several neurodegenerative diseases, which is thought to play a major role in disease severity and progression. The principal machineries maintaining proteostasis are the ubiquitin proteasomal and lysosomal autophagy systems, where heat shock proteins play a crucial role. Many protein aggregates are degraded by the lysosomes, depending on aggregate size, peptide sequence, and degree of misfolding, while others are selectively tagged for removal by heat shock proteins and degraded by either the proteasome or phagosomes. These systems are compromised in different neurodegenerative diseases. Therefore, developing novel targets and classes of therapeutic drugs, which can reduce aggregates and maintain proteostasis in the brains of neurodegenerative models, is vital. Natural products that can modulate heat shock proteins/proteosomal pathway are considered promising for treating neurodegenerative diseases. Here we discuss the current knowledge on the role of HSPs in protein misfolding diseases and knowledge gained from animal models of Alzheimer’s disease, tauopathies, and Huntington’s diseases. Further, we discuss the emerging treatment regimens for these diseases using natural products, like curcumin, which can augment expression or function of heat shock proteins in the cell.

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Neurodegenerative disease-associated protein aggregates are poor inducers of the heat shock response in neuronal-like cells

10.1101/2020.01.06.896654 ◽

2020 ◽

Cited By ~ 1

Author(s):

R. San Gil ◽

D. Cox ◽

L. McAlary ◽

T. Berg ◽

A. K. Walker ◽

...

Keyword(s):

Heat Shock ◽

Heat Shock Proteins ◽

Neurodegenerative Diseases ◽

Protein Aggregation ◽

Neurodegenerative Disease ◽

Heat Shock Response ◽

Flow Cytometric Analysis ◽

Protein Aggregates ◽

Shock Response ◽

Shock Proteins

AbstractProtein aggregation that results in the formation of inclusions is strongly correlated with neuronal death and is a pathological hallmark common to many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and Huntington’s disease. Cells are thought to dramatically up-regulate the levels of heat shock proteins during periods of cellular stress via induction of the heat shock response (HSR). Heat shock proteins are well-characterised molecular chaperones that interact with aggregation-prone proteins to either stabilise, refold, or traffic protein for degradation. The reason why heat shock proteins are unable to maintain the solubility of particular proteins in neurodegenerative disease is unknown. We sought to determine whether neurodegenerative disease-associated protein aggregates can induce the HSR. Here, we generated a neuroblastoma cell line that expresses a fluorescent reporter under conditions of HSR induction, for example heat shock. Using these cells, we show that the HSR is not induced by exogenous treatment with aggregated forms of Parkinson’s disease-associated α-synuclein or the ALS-associated G93A mutant of superoxide dismutase-1 (SOD1G93A). Furthermore, flow cytometric analysis revealed that intracellular expression of SOD1G93A or a pathogenic form of polyQ-expanded huntingtin (Htt72Q), similarly, results in no or low induction of the HSR. In contrast, expression of a non-pathogenic but aggregation-prone form of firefly luciferase (Fluc) did induce an HSR in a significantly greater proportion of cells. Finally, we show that HSR induction is dependent on the intracellular levels of the aggregation-prone proteins, but the pathogenic proteins (SOD1G93A and Htt72Q) elicit a significantly lower HSR compared to the non-pathogenic proteins (Fluc). These results suggest that pathogenic proteins either evade detection or impair induction of the HSR in neuronal-like cells. Therefore, defective HSR induction may facilitate the initiation of protein aggregation leading to inclusion formation in neurodegenerative diseases.

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Extracellular vesicle-associated small heat shock proteins as therapeutic agents in neurodegenerative diseases and beyond

Advanced Drug Delivery Reviews ◽

10.1016/j.addr.2021.114009 ◽

2021 ◽

pp. 114009

Author(s):

Bram Van den Broek ◽

Charlotte Wuyts ◽

Joy Irobi

Keyword(s):

Heat Shock ◽

Heat Shock Proteins ◽

Neurodegenerative Diseases ◽

Extracellular Vesicle ◽

Therapeutic Agents ◽

Small Heat Shock Proteins ◽

Shock Proteins

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The Role of Heat Shock Proteins in the Mechanisms of Neurodegeneration and Neuroprotection in Primary Glaucoma: Literature Review

International scientific-practical journal Ophthalmology ◽

10.30702/ophthalmology31032021-12.1.122-131/112.5 ◽

2021 ◽

pp. 122-131

Author(s):

N. S. Lutsenko ◽

T. V. Nedilka

Keyword(s):

Heat Shock ◽

Heat Shock Proteins ◽

Neurodegenerative Diseases ◽

Retinal Ganglion Cells ◽

Defense Mechanism ◽

Ganglion Cells ◽

The Body ◽

Retinal Ganglion ◽

Shock Proteins

Heat shock proteins (HSP) are important components of the defense mechanism that increases the survival of body cells in adverse conditions due to antiapoptotic and cytoprotective effects. Since their discovery, numerous studies and experimental models have proved the role of HSPs as a key link in the processes of both repair and coagulation of proteins, as well as in the protection of cells from oxidative stress. The potential for pharmacological induction of HSPs in the human body makes them an attractive therapeutic target for many neurodegenerative diseases. This review examines the role of HSPs, especially fraction 70, in the mechanisms of neuroprotection of retinal ganglion cells in primary open-angle glaucoma being one of the common neurodegenerative diseases that can lead to complete loss of visual functions. A number of studies have shown the protective effect of HSP70 on retinal ganglion cells in animals with artificially induced glaucoma. But in the course of experiments on animal models, it was also proved that direct immunization with HSP through intravitreal injections induced pressure-independent degeneration of retinal ganglion cells. This indicates the need for indirect stimulation of HSP70 in order to activate their neuroprotective properties. To date, there are insufficient data on the circulation of HSP70 in the body of a person with glaucoma. These data indicate the prospects for further study of the role of HSP70 in glaucoma degeneration and elucidation of the ways of their mediated induction. Keywords: heat shock protein, HSP70, glaucoma, ganglion cells, retina, neuroprotection.

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