Heat shock proteins: cellular and molecular mechanisms in the central nervous system

Abstract

Emerging evidence indicates that heat shock proteins (HSPs) are critical regulators in normal neural physiological function as well as in cell stress responses. The functions of HSPs represent an enormous and diverse range of cellular activities, far beyond the originally identified roles in protein folding and chaperoning. HSPs are now understood to be involved in processes such as synaptic transmission, autophagy, ER stress response, protein kinase and cell death signaling. In addition, manipulation of HSPs has robust effects on the fate of cells in neurological injury and disease states. The ongoing exploration of multiple HSP superfamilies has underscored the pluripotent nature of HSPs in the cellular context, and has demanded the recent revamping of the nomenclature referring to these families to reflect a re-organization based on structure and function. In keeping with this re-organization, we first discuss the HSP superfamilies in terms of protein structure, regulation, expression and distribution in the brain. We then explore major cellular functions of HSPs that are relevant to neural physiological states, and from there we discuss known and proposed HSP impacts on major neurological disease states. This review article presents a three-part discussion on the array of HSP families relevant to neuronal tissue, their cellular functions, and the exploration of therapeutic targets of these proteins in the context of neurological diseases.

Figure 1

Major protein domains defining HSP families.

Figure 2. ER unfolded protein response and protein degradation pathways mediated by HSPs

Aberrantly folded proteins in the ER are recognized and bound by HSPA5/BiP, which disengages from the luminal side of a transmembrane complex, and allows activation of stress signaling pathways to the nucleus (A). If the refolding system is overwhelmed, misfolded proteins are targeted to the ER-associated degradation path (ERAD) (B), where they are secreted to the cytosol via recognition by HSPA and DNAJ (green J) proteins and shuttled to the proteasomal system (C). Classical protein degradation mediated by the ubiquitin-proteasome system (UPS) involves the recognition of targeted proteins by either HSPA (red squares) or HSPC (yellow triangles) and appropriate co-factor binding. Cytosolic proteins containing a KFERQ motif may also be recognized by HSPA proteins and targeted to a lysosomal complex containing HSPC and LAMP2A (D). The proteins are imported into lysosomes, where they are bound by an intralysosomal HSPA member for unfolding and degradation by hydrolases. HSPB family members may also be involved in autophagy by binding to targeted proteins (E). HSPB then complexes with the co-chaperone Bag-3, which recruits nearby autophagic machinery.

Figure 3. Synaptic functions of HSP family members

HSPA (red squres) and DNAJ families have described roles in presynaptic vesicular release, clathrin uncoating, endosomal cycling and postsynaptic receptor clustering. DNAJC5/CSPa interacts with the SNARE complex and recruits several co-factors, including HSPA8/Hsc70, leading to the fusion of vesicles to the synaptic membrane. In turn, DNAJC6/auxilin binds clathrin-coated vesicles during vesicular reuptake, recruits HSPA8 and leads to clathrin removal. Endosomal trafficking requires DNAJC13/Rme-8, but the mechanism remains unclear. In addition to presynaptic effects, the clustering of acetylcholine receptors requires DNAJA3/Tid1. Ablation of AChR clustering disorganizes nerve terminals, leading to dysfunctional neuromuscular junction formation.

Figure 4. Mitochondrial chaperone-mediated protein import and folding

Nuclear-encoded mitochondrial-targeted proteins are synthesized outside of the mitochondria and targeted by HSPA (red squares) to the TOM complex located on the outer mitochondrial membrane. The protein is unfolded, passed through the TIM complex transversing the inner mitochondrial membrane, and received by the mitochondrial-resident HSPA/mortalin. The protein is then refolded after cleavage of the mitochondrial-localization signal to its final state by the mitochondrial chaperone HSPD (blue circle) and its co-chaperone, HSPE (orange pentagon).

Figure 5. HSP interaction with cell death signaling

Both HSPA (red squares) and HSPB (green triangles) family members have been implicated at various levels in suppression of cell death signaling. HSPA and HSPB directly suppress ASK-1 activity, which leads to suppression of mitochondrial cell death signaling. Furthermore, HSPB suppresses DAXX-mediated Bid translocation to the mitochondria, whereas HSPA suppresses upstream of Bax mitochondrial translocation. Downstream of mitochondrial signaling, HSPB can suppress the activation of caspase-9 or -3. HSPA both inhibited apoptosome formation as well as suppressed the nuclear translocation of the apoptosis-inducing factor (AIF). These activities lead to suppression of cell death.