The Mitochondrial Hsp90 TRAP1 and Alzheimer’s Disease

Abstract

Alzheimer’s Disease (AD) is the most common form of dementia, characterised by intra- and extracellular protein aggregation. In AD, the cellular protein quality control (PQC) system is derailed and fails to prevent the formation of these aggregates. Especially the mitochondrial paralogue of the conserved Hsp90 chaperone class, tumour necrosis factor receptor-associated protein 1 (TRAP1), is strongly downregulated in AD, more than other major PQC factors. Here, we review molecular mechanism and cellular function of TRAP1 and subsequently discuss possible links to AD. TRAP1 is an interesting paradigm for the Hsp90 family, as it chaperones proteins with vital cellular function, despite not being regulated by any of the co-chaperones that drive its cytosolic paralogues. TRAP1 encloses late folding intermediates in a non-active state. Thereby, it is involved in the assembly of the electron transport chain, and it favours the switch from oxidative phosphorylation to glycolysis. Another key function is that it ensures mitochondrial integrity by regulating the mitochondrial pore opening through Cyclophilin D. While it is still unclear whether TRAP1 itself is a driver or a passenger in AD, it might be a guide to identify key factors initiating neurodegeneration.

All Roads Lead to Rome: Different Molecular Players Converge to Common Toxic Pathways in Neurodegeneration

“…For example, HSP90 mediates transcription of APP and proteins involved in synaptic plasticity, and the cytosolic HSP90 controls tau levels. Moreover, HSP90 cooperates with the E3 ubiquitin ligase CHIP to target tau for proteasomal degradation [ 108 ]. Furthermore, HSP90 inhibits Aβ toxicity by binding misfolded Aβ peptides and preventing further aggregation using an ATP-independent pathway or by changing the conformation of Aβ to a state that is less prone to aggregation via an ATP-dependent pathway [ 109 ].…”

“…Furthermore, HSP90 inhibits Aβ toxicity by binding misfolded Aβ peptides and preventing further aggregation using an ATP-independent pathway or by changing the conformation of Aβ to a state that is less prone to aggregation via an ATP-dependent pathway [ 109 ]. However, HSP90 levels are reduced in AD, especially in the hippocampus, entorhinal cortex, and cingulate gyrus, which are the most affected in AD [ 108 ]. Another involved HSP is HSP104, which inhibits the fibrillization of monomeric and protofibrillar forms of Aβ in a concentration-dependent but ATP-independent manner [ 110 ].…”

TRAP1 in Oxidative Stress and Neurodegeneration

“…The human TRAP1 gene locus resides on chromosome 16p13, spans 60 kb, and includes 18 exons. The main TRAP1 transcript composed of 2,112 bp, encodes a protein of 704 amino acids [ 9 ] containing three major domains: NTD, MD and CTD ( Figure 1 ), as previously mentioned [ 2 , 3 , 10 ].…”

“…The mitochondrial chaperone TRAP1 is an important modulator of the mitochondrial energy metabolism including oxidative phosphorylation (OXPHOS) processes [ 9 , 31 , 35 , 36 ], and it operates by interacting with proteins of the mitochondrial electron transport chain (ETC), as well as succinate dehydrogenase (SDH) and cytochrome oxidase, also known, respectively, as complex II and complex IV. It also acts as a key regulator of the protein quality control (PQC) [ 2 , 9 , 25 , 31 ].…”

“…The prototypic HSP90 family member has three structural domains, namely, an N-terminal domain (NTD) responsible for ATP binding, a middle domain (MD) which is important for binding clients and the ɣ-phosphate of ATP, and a C-terminal domain (CTD) responsible for dimerization. Like other chaperones, HSP90 family members are important for the folding of client protein substrates, as well as the degradation of the misfolded proteins [ 2 , 3 ].…”