Hsp90 Modulation for the Treatment of Alzheimer’s Disease
Introduction
Nearly all age-dependent neurodegenerative diseases are characterized by the accumulation of misfolded proteins that form distinctive types of aggregates within or outside the brain or spinal cord neurons and glia, a process often called “proteotoxicity.” Although the presence of these neuropathological lesions was used for many years to establish a definitive diagnosis for diseases such as Alzheimer’s disease, it has only been within the past three decades that the actual proteins found in the brain lesions have been identified. We now know that the “senile plaques” of Alzheimer’s disease (AD) are primarily composed of aggregates of a 40–42-amino acid peptide (Aβ) derived from the large amyloid precursor protein (APP) by sequential proteolysis (Glenner & Wong, 1984). Neurofibrillary tangles (NFT), the second lesion characteristic of AD neuropathology, are composed of fibrils of hyper-phosphorylated Tau—a microtubule-associated protein (Grundke-Iqbal et al., 1986). Parkinson’s disease, the second most common progressive neurodegenerative disorder, leads to the development of Lewy bodies composed primarily of fibrillar α-synuclein (Spillantini & Goedert, 1998). The identities of aggregated proteins in some less frequent, but equally debilitating nervous system diseases are also known. These include diseases such as Huntington disease with aggregates of the polyglutamine-rich protein huntingtin (DiFiglia et al., 1997), amyotrophic lateral sclerosis (ALS) with inclusions of superoxide dismutase1 (SOD1) (Bruijn et al., 1998) and the RNA/DNA binding protein TDP-43 (Arai et al., 2006; Neumann et al., 2006), the spongiform encephalopathies with prion protein aggregates (Bolton et al., 1982), and the “Tauopathies” with fibrillar aggregates of mutated Tau (Lee et al., 2001). Proteins associated with these neurodegenerative diseases do not share obvious sequence or structural homology and, in fact, appear in different cell types and in different regions of the central nervous system (CNS). It is this diversity that gives rise to the early clinical picture that emerges in patients with these diseases. Nevertheless, these conformational diseases do have some characteristics in common.
Current research on the properties manifested by proteins found in the conformational diseases has revealed that most are monomers that undergo conversion from α-helical structures to misfolded β-sheet-containing proteins that are strongly prone to self-aggregation and become pathogenic. It appears that the proteins initially form oligomers that act as seeds to promote further misfolding by serving as templates to catalyze the growth of polymers. As the nucleation process progresses, the polymers become insoluble and are eventually deposited in the brain tissue, forming plaques, tangles, Lewy bodies, and other inclusions characteristic of specific neurodegenerative diseases (Soto & Estrada, 2008). However, much evidence now supports the hypothesis that, at least for Aβ, the intermediates or soluble oligomers are the toxic species that actually lead to synaptic dysfunction and challenge neuronal viability (Walsh & Selkoe, 2007). The deposits may result from the failure to control aggregation or to sequester insoluble assemblies outside the neurons. Therefore, maintaining solubility or facilitating the disposal of such oligomers is the challenge faced by the cells’ protein quality machinery. Not surprisingly, many drug discovery efforts are now underway to design strategies for optimizing the functions of that cellular machinery.
Perhaps the most important characteristic shared by the protein conformational diseases is their association with the process of aging. The major risk factor associated with the emergence of clinical signs and symptoms of diseases such as AD is increased age. It is true that mutations in the genes for several of the misfolded proteins lead to familial forms of the diseases with an earlier onset, but the vast majority of cases are sporadic and emerge late in life. So what is it about the aging process that makes the brain vulnerable to “proteotoxicity?” Certainly no clear answer exists at this time, but the question has sent scientists on a quest to understand the systems that cells use to maintain protein quality control across the lifespan, namely the systems that fold nascent proteins, monitor the state of extant proteins, and refold or induce degradation of those that are misfolded. These investigative efforts have led to a wealth of new information about the vast network of the “molecular chaperones” and the pathways through which they enable cell protection against proteotoxic stresses (Kopito & Ron, 2000; Powers et al., 2009). The molecular chaperones, many of which are called “heat shock proteins (Hsps),” are ubiquitous and highly conserved proteins at the center of conformational homeostasis, and substantial evidence indicates that these systems become less efficient with age, possibly due to enhanced oxidative stress, which leads to oxidation and nitration of proteins, including the chaperones themselves. Such conditions could easily overload the system and allow for the accumulation of more misfolded proteins (Cuervo & Dice, 2000; Lund et al., 2002; Tonoki et al., 2009). Enhancing the protein quality control capacity by elevating chaperone protein expression is one approach toward halting or reversing the deterioration process associated with aging. Since Hsp expression is tightly regulated by heat shock factor 1 (HSF-1), the discovery of new molecules that induce expression is likely to provide agents that can protect the brain against devastating neurodegenerative cascades. Extensive research efforts including genetic and high-throughput screening approaches have identified a handful of genetic and chemical activators of HSF-1 (Calamini et al., 2012; Neef et al., 2010; Santagata et al., 2012; Silva et al., 2011,). Although indirect activation of HSF-1 by modulating posttranslational modifications such as phosphorylation, sumoylation, acetylation, direct activation of HSF-1 by interfering with protein–protein interactions, or the promotion of HSF-1 trimerization have been proposed (Neef et al., 2011), pharmacologically activating HSF-1 by suppressing the proteins that negatively regulate HSF-1 function is the most well-characterized approach. Since HSF-1 activation is tightly regulated by heat shock protein 90 (Hsp90), one promising strategy is the development of small molecules that modulate Hsp90, which acts in concert with other chaperones, transcription factors, kinases, binding partners, and substrates to maintain cellular “proteostasis” (http://www.picard.ch/downloads/Hsp90facts.pdf). This review is focused on efforts to develop potential therapeutic agents that target the Hsp90 protein folding machinery as a novel approach toward the treatment of AD and related neurodegenerative diseases.
Section snippets
Hsp90 Complexes in Alzheimer’s Disease
Hsps represent a large family of molecular chaperones that are highly conserved across a wide array of organisms, ranging from bacteria to homosapiens (Blagg & Kerr, 2006; Richter & Buchner, 2006). As a cell-protective mechanism, Hsps are capable of modulating the proper folding of nascent polypeptides, assisting the refolding of denatured proteins, and directing damaged proteins to the ubiquitin-proteasome pathway for degradation. Together, these processes maintain the cell protein homeostasis
Hsp90 N-Terminal Inhibitors
Hsp90 inhibitors have been developed for cancer treatment based on the fact that inhibition of the Hsp90 protein folding machinery results in simultaneous disruption of multiple oncogenic pathways that are critical to malignant growth and proliferation (Biamonte et al., 2010; Blagg & Kerr, 2006; Kim et al., 2009). Geldanamycin (GDA, Fig. 3) was the first natural product inhibitor of Hsp90 identified, and this opened the door to an entirely new area of anticancer research. GDA continues to serve
Conclusion
Because AD is an age-related disease, the incidence of disease is expected to increase at an unprecedented rate that parallels the aging population. Although extensive efforts have been made toward identification of a cure for this disease, the looming fate of AD victims is largely unchanged and the exact mechanisms for the onset of this disease remain largely unsolved. After 30 years of research, it has been determined that AD is a multimechanistic disease and that targeting one specific
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