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Related Experiment Video

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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.

Neuron
|January 28, 2014
PubMed
Summary
This summary is machine-generated.

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.

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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.