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Updated: May 3, 2026
Using Caenorhabditis elegans to Screen for Tissue-Specific Chaperone Interactions
Published on: June 7, 2020
Age-dependent decrease in chaperone activity impairs MANF expression, leading to Purkinje cell degeneration in
Su Yang1, Shanshan Huang2, Marta A Gaertig1
1Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Room 355, Atlanta, GA 30322, USA.
Abstract:
Although protein-misfolding-mediated neurodegenerative diseases have been linked to aging, how aging contributes to selective neurodegeneration remains unclear. We established spinocerebellar ataxia 17 (SCA17) knockin mice that inducibly express one copy of mutant TATA box binding protein (TBP) at different ages by tamoxifen-mediated Cre recombination. We find that more mutant TBP accumulates in older mouse and that this accumulation correlates with age-related decreases in Hsc70 and chaperone activity. Consistently, older SCA17 mice experienced earlier neurological symptom onset and more severe Purkinje cell degeneration. Mutant TBP shows decreased association with XBP1s, resulting in the reduced transcription of mesencephalic astrocyte-derived neurotrophic factor (MANF), which is enriched in Purkinje cells. Expression of Hsc70 improves the TBP-XBP1s interaction and MANF transcription, and overexpression of MANF ameliorates mutant TBP-mediated Purkinje cell degeneration via protein kinase C (PKC)-dependent signaling. These findings suggest that the age-related decline in chaperone activity affects polyglutamine protein function that is important for the viability of specific types of neurons.
Insights
Aging reduces chaperone activity, increasing mutant TATA box binding protein (TBP) accumulation. This accelerates neurodegeneration in spinocerebellar ataxia 17 (SCA17) mice by impairing neuron-protective factor production.
Area of Science:
- Neuroscience
- Aging Research
- Genetics
Background:
- Protein misfolding is linked to neurodegenerative diseases and aging.
- The precise mechanisms by which aging exacerbates selective neurodegeneration are not fully understood.
Purpose of the Study:
- To investigate how aging influences the accumulation and toxicity of mutant TATA box binding protein (TBP) in spinocerebellar ataxia 17 (SCA17).
- To elucidate the role of chaperone activity and neurotrophic factors in age-dependent neurodegeneration.
Main Methods:
- Generation of SCA17 knockin mice with inducible mutant TBP expression at various ages.
- Assessment of mutant TBP accumulation, chaperone activity (Hsc70), and Purkinje cell degeneration.
- Analysis of TBP-XBP1s interaction and mesencephalic astrocyte-derived neurotrophic factor (MANF) transcription.
- Investigating the therapeutic potential of Hsc70 and MANF.
Main Results:
- Older SCA17 mice exhibited increased mutant TBP accumulation, decreased Hsc70 levels, and reduced chaperone activity.
- Older mice showed earlier symptom onset and more severe Purkinje cell loss.
- Mutant TBP impaired XBP1s association, reducing MANF transcription.
- Hsc70 expression restored TBP-XBP1s interaction and MANF transcription; MANF overexpression protected Purkinje cells.
Conclusions:
- Age-related decline in chaperone activity exacerbates mutant TBP toxicity in SCA17 mice.
- Reduced MANF levels contribute to Purkinje cell degeneration in this model.
- Restoring chaperone function or enhancing MANF signaling may offer therapeutic strategies for age-related neurodegenerative diseases.
