Heat Shock Proteins and the Brain: Implications for Neurodegenerative Diseases and Neuroprotection

We have investigated the developmental expression of the small heat-shock proteins (hsps) during embryogenesis and in adult flies by immunocytology using an antibody that specifically identifies the small hsps. Antibody staining of unstressed early embryos reveals a predominantly cytoplasmic, homogeneous distribution of the small hsps throughout the embryo. At 6h of development small hsp expression can be identified in large, neuroblast-like cells within the extended germ band and in the brain of the embryo. During germ band contraction these cells appear to migrate to the midline where they align pairwise in a segmental pattern. After germ band contraction is complete a high level of small hsp expression can be observed in the midline glia (MECs) and in a cluster of six non-neuronal cells within the midline. In contrast to several other genes that are known to be important for embryogenesis and are expressed in the central nervous system (CNS) of embryos, CNS-specific expression of the small hsps is not restricted to the embryo but is also observed in the adult fly. In adult flies strong small hsp expression is observed in the brain, the thoracic ganglion and the leg nerves. Since the small hsps seem to be expressed predominantly in the glia of the nervous system, our data suggest a protective or stabilizing function of the small hsps within the nervous system during normal fly development, which is independent of the stress response.

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Tissue-specific patterns of synthesis of heat-shock proteins and thermal tolerance of the fathead minnow (Pimephales promelas)

Canadian Journal of Zoology ◽

10.1139/z91-282 ◽

1991 ◽

Vol 69 (8) ◽

pp. 2021-2027 ◽

Cited By ~ 52

Author(s):

Scott D. Dyer ◽

Kenneth L. Dickson ◽

Earl G. Zimmerman ◽

Brenda M. Sanders

Keyword(s):

Heat Shock ◽

Heat Shock Proteins ◽

Brain Tissue ◽

Fathead Minnow ◽

Pimephales Promelas ◽

Gill Tissue ◽

Tissue Specific ◽

Thermal Limits ◽

Shock Proteins ◽

The Brain

Qualitative and quantitative differences in the heat-shock response in brain, gill, and striated muscle tissues of the fathead minnow (Pimephales promelas) were investigated. The maximum sublethal heat-shock temperature was 34 °C. The heat-shock proteins (hsps) induced, their biosynthetic rates, minimum temperatures required for induction, and maximum temperatures at which each tissue synthesized hsps were tissue specific. Six hsps were induced in gill tissue (100, 90, 78, 70, 68, and 60 kDa), four in muscle tissue (100, 90, 78, and 70 kDa), and three in brain tissue (90, 70, and 68 kDa). Minimum temperatures required for inducing the stress response in gill, muscle, and brain were 28, 31, and 32 °C, respectively. Maximum hsp synthesis and accumulation occurred at 33 °C for the brain and 34°C for muscle and gill. Synthesis and accumulation of hsps decreased to near pre-exposure levels in the brain at 34 °C. The fact that brain tissue synthesized the fewest hsps and had the lowest capacity for synthesis at the upper thermal limits of the organism supports the hypothesis that the central nervous system governs the thermal limits to survival in poikilotherms.

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Molecular Chaperone Dysfunction in Neurodegenerative Diseases and Effects of Curcumin

BioMed Research International ◽

10.1155/2014/495091 ◽

2014 ◽

Vol 2014 ◽

pp. 1-14 ◽

Cited By ~ 63

Author(s):

Panchanan Maiti ◽

Jayeeta Manna ◽

Shobi Veleri ◽

Sally Frautschy

Keyword(s):

Natural Products ◽

Heat Shock ◽

Heat Shock Proteins ◽

Neurodegenerative Diseases ◽

Protein Misfolding ◽

Current Knowledge ◽

Aggregate Size ◽

Peptide Sequence ◽

Treatment Regimens ◽

Shock Proteins

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

Journal of Neuroimmunology ◽

10.1016/0165-5728(94)90302-6 ◽

1994 ◽

Vol 54 (1-2) ◽

pp. 159

Author(s):

U. Fiszer ◽

S. Fredrikson ◽

J. Gajda ◽

A. Czlonkowska

Keyword(s):

Heat Shock ◽

Heat Shock Proteins ◽

Neurodegenerative Diseases ◽

Shock Proteins

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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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