Abstract
Hyperphosphorylation of protein tau is a hallmark of Alzheimer’s disease (AD). Changes in energy and lipid metabolism have been correlated with the late onset of this neurological disorder. However, it is uncertain if metabolic dysregulation is a consequence of AD or one of the initiating factors of AD pathophysiology. Also, it is unclear whether variations in lipid metabolism regulate the phosphorylation state of tau. Here, we show that in humanized yeast, tau hyperphosphorylation is stimulated by glucose starvation in coincidence with the downregulation of Pho85, the yeast ortholog of CDK5. Changes in inositol phosphate (IP) signaling, which has a central role in energy metabolism, altered tau phosphorylation. Lack of inositol hexakisphosphate kinases Kcs1 and Vip1 (IP6 and IP7 kinases in mammals) increased tau hyperphosphorylation. Similar effects were found by mutation of IPK2 (inositol polyphosphate multikinase), or PLC1, the yeast phospholipase C gene. These effects may be explained by IP-mediated regulation of Pho85. Indeed, this appeared to be the case for plc1, ipk2, and kcs1. However, the effects of Vip1 on tau phosphorylation were independent of the presence of Pho85, suggesting additional mechanisms. Interestingly, kcs1 and vip1 strains, like pho85, displayed dysregulated sphingolipid (SL) metabolism. Moreover, genetic and pharmacological inhibition of SL biosynthesis stimulated the appearance of hyperphosphorylated forms of tau, while increased flux through the pathway reduced its abundance. Finally, we demonstrated that Sit4, the yeast ortholog of human PP2A protein phosphatase, is a downstream effector of SL signaling in mediating the tau phosphorylation state. Altogether, our results add new knowledge on the molecular effectors involved in tauopathies and identify new targets for pharmacological intervention.
Highlights
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease being responsible for 60–70% of the 50 million cases of dementia every year (Prince et al, 2015)
It has been reported that IP6K3 variants that increase the production of diphosphoinositol phosphate (DPIP) IP7, impact on neuronal energy homeostasis and increase the risk of sporadic late-onset Alzheimer’s disease (LOAD) (Crocco et al, 2016)
We examined the relationship between tau phosphorylation, energy metabolism, and inositol hexakisphosphate kinases, Kcs1 and Vip1, in our yeast model system using the CEN.PK2-1C genetic background
Summary
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease being responsible for 60–70% of the 50 million cases of dementia every year (Prince et al, 2015). Current treatments for AD remain supportive, without changing the life expectancy or overall progression of dementia (Weller and Budson, 2018). Understanding the molecular mechanisms that result in this neurodegenerative disorder has been and remains of major importance. The neurodegenerative process in AD is characterized by the progressive accumulation of amyloid plaques, mainly composed of amyloid-beta peptides (Aβ), and neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau (Jeong, 2017). The amyloid plaques accumulate extracellularly in the brains of AD patients and are generated by sequential processing of the amyloid precursor protein, APP (Glenner et al, 1984; Dyrks et al, 1988). The neurofibrillary tangles are found inside neurons and consist of an abnormally phosphorylated form of the tau protein (Buée et al, 2000). Reducing self-assembled hyperphosphorylated tau might be pivotal to alleviate tau deposition and confer resistance to Aβ-mediated neurodegeneration
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