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UBB+1-induced activation of autophagy reduces cytotoxicity of amyloid-β in yeast

ABSTRACT: UBB+1 is a mutated version of ubiquitin B caused by a transcriptional frameshift. The accumulation of UBB+1, has been linked to ubiquitin-proteasome system (UPS) dysfunction and neurodegeneration. Alzheimer’s disease (AD) is the most common form of neurodegeneration and accumulation of amyloid β (Aβ) in the brain is a prominent neuropathological feature of AD. In our previous study, we found that low expression of UBB+1 could protect cells against several stresses during chronological aging. Here, we applied the genome-wide expression analyses and found that low UBB+1 expression activated the autophagy pathway. Low UBB+1 expression was shown to upregulate vacuolar activity and promote transport of the ATG8p (autophagic marker) to the vacuole. To further study the effects, we expressed low level of UBB+1 in our humanized yeast Aβ models with the expression of either Aβ42 or Aβ40. Interestingly, the co-expression of UBB+1 with Aβ42 or Aβ40 showed a reduction of intracellular Aβ levels and increased chronological life span. In the autophagy deficient mutant background (atg1∆), the intracellular Aβ levels were not affected by UBB+1 expression. Our findings suggest a mechanism of UBB+1 action in reducing intracellular levels of Aβ.

ORGANISM(S): Saccharomyces cerevisiae Schizosaccharomyces pombe

PROVIDER: GSE129688 | GEO | 2021/03/12

REPOSITORIES: GEO

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Project description:Gamma oscillations (20-50Hz) are a common local field potential signature in many brain regions that are generated by a resonant circuit between fast-spiking parvalbumin (PV)-positive interneurons and pyramidal cells. Changes in the magnitude and frequency of gamma have been observed in several neuropsychiatric disorders. However, it is unclear how disruptions in gamma oscillations affect cellular pathologies seen in these disorders. Here, we investigate this using the 5XFAD mouse model of Alzheimer’s disease (AD) and find reduced power and magnitude of behaviorally driven gamma oscillatory activity — even before the onset of plaque formation or measurable cognitive decline. Because of the early onset, we aimed to determine if exogenous manipulations of gamma could influence the progression of disease pathology. We find that driving PV-positive neurons at gamma frequency (40Hz) using channelrhodopsin-2 reduced total levels of amyloid-β (Aβ) 40 and 42 isoforms in the hippocampus of 5XFAD mouse. Driving PV-positive neurons at other frequencies, or driving excitatory neurons, did not reduce Aβ levels. Furthermore, driving PV-positive neurons reduced enlarged endosomes in hippocampal neurons and cleavage intermediates of APP in 5XFAD mouse. Gene expression profiling revealed a neuroprotective response with morphological transformation of microglia and markedly increased phagocytosis of Aβ by microglia. Inspired by these observations, we designed a non-invasive light-flickering paradigm that drives 40Hz gamma activity in mouse visual cortex. The light-flickering paradigm profoundly reduced Aβ40 and Aβ42 levels in the visual cortex of pre-symptomatic mice and greatly mitigated plaque load in the visual cortex of aged, symptomatic mice. This reduction was completely blocked by a GABA-A antagonist, providing further support for an essential role of GABAergic signaling in mediating neuroprotective gamma activity. Overall, our findings uncover a dramatic and previously unappreciated function of the brain’s endogenous gamma rhythms in reducing the production and increasing the clearance of Aβ peptides, whose accumulation is believed to drive the pathogenesis of AD.

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UBB+1-induced activation of autophagy reduces cytotoxicity of amyloid-β in yeast

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