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.
Highlights
Alzheimer’s Disease (AD) is characterised by progressive cognitive decline (Goedert and Spillantini, 2006; Crews and Masliah, 2010; Weller and Budson, 2018)
tumour necrosis factor receptor-associated protein 1 (TRAP1) and Alzheimer’s Disease hallmarks of AD are two protein aggregates found in the brain; β-amyloid (Aβ) forming extracellular senile plaques (SPs) and Tau proteins forming neurofibrillary tangles (NFTs) inside the cell (Kidd 1963; Ittner and Götz, 2011; Panza et al, 2019)
We describe the Hsp90 family and how it functions in the Protein Quality Control (PQC) system, and we discuss mechanism and structure of TRAP1 in particular
Summary
Alzheimer’s Disease (AD) is characterised by progressive cognitive decline (Goedert and Spillantini, 2006; Crews and Masliah, 2010; Weller and Budson, 2018). For TRAP1, there is a functional implication of tetramer formation, related to a role in metabolic regulation in the mitochondria (Joshi et al, 2020). Considering the function of Sorcin ER paralogue, the 18 kDa isoform may have a role in Ca2+-homeostasis in the mitochondria, possibly by regulating the mitochondrial PTP.
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