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Neuronal aging leads to disrupted RNA metabolism

ABSTRACT: Aging is one of the most prominent risk factors for neurodegeneration, yet the molecular mechanisms underlying the deterioration of old neurons are mostly unknown. To efficiently study neurodegeneration in the context of aging, we transdifferentiated primary human fibroblasts from aged (i.e. >50 year-old) healthy donors directly into neurons, which retained their aging-associated phenotypes including senescence and dysregulation of CpG methylation. Here we show that aged neurons are broadly depleted of RNA-binding proteins, especially 26 spliceosome components. Intriguingly, splicing proteins – like the dementia and ALS-associated protein TDP-43 – mislocalize to the cytoplasm in aged neurons, which leads to widespread alternative splicing. Although spliceosome components can be sequestered within cytoplasmic stress granules, we find that aged neurons suffer from chronic stress that leads to the segregation of stress granule and spliceosome RNA-binding proteins. We link chronic stress to the accumulation of misfolded proteins and to poor HSP90α chaperone activity. Importantly, we also show that aged neurons respond poorly to acute stress treatments, leading to long-term retention of stress granules and failure to initiate transcription of stress-related heat shock proteins. Together our data demonstrates that dysregulation of RNA metabolism is a key driver of poor resiliency in aged neurons.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Xuezhen Ge

LAB HEAD: Gene W. Yeo

PROVIDER: PXD055904 | Pride | 2025-02-19

REPOSITORIES: pride

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			Action	DRS
	P001739_G3BP1_AP_MS_peptides.txt	Txt
	P001739_K17a_Ngn2_S1.raw	Raw
	P001739_K17a_Ngn2_S2.raw	Raw
	P001739_K17a_Ngn2_U1.raw	Raw
	P001739_K17a_Ngn2_U2.raw	Raw

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Project description:Deficits in chemosensory processing are associated with healthy aging, as well as numerous neurodegenerative disorders, including Alzheimer’s Disease (AD). In many cases, chemosensory deficits are harbingers of neurodegenerative disease, and understanding the mechanistic basis for these changes may provide insight into the fundamental dysfunction associated with aging and neurodegeneration. The fruit fly, Drosophila melanogaster, is a powerful model for studying chemosensation, aging, and aging-related pathologies, yet the effects of aging and neurodegeneration on chemosensation remain largely unexplored in this model, particularly with respect to taste. To determine whether the effects of aging on taste are conserved in flies, we compared the response of flies to different appetitive tastants. Aging impaired response to sugars, but not medium-chain fatty acids that are sensed by a shared population of neurons, revealing modality-specific deficits in taste. Selective expression of the human amyloid beta (Ab) 1-42 peptide bearing the Arctic mutation (E693E) associated with early onset AD in the neurons that sense sugars and fatty acids phenocopies the effects of aging, suggesting that the age-related decline in response is localized to gustatory neurons. Functional imaging of gustatory axon terminals revealed reduced response to sugar, but not fatty acids. Axonal innervation of the fly taste center was largely intact in aged flies, suggesting that reduced sucrose response does not derive from neurodegeneration. Conversely, expression of the amyloid peptide in sweet-sensing taste neurons resulted in reduced innervation of the primary fly taste center. A comparison of transcript expression within the sugar-sensing taste neurons revealed age-related changes in 66 genes, including a reduction in odorant-binding protein class genes that are also expressed in taste sensilla. Together, these findings suggest that deficits in taste detection may result from signaling pathway-specific changes, while different mechanisms underly taste deficits in aged and AD model flies. Overall, this work provides a model to examine cellular deficits in neural function associated with aging and AD.

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Neuronal aging leads to disrupted RNA metabolism

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