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Published on: March 12, 2018
Hsc70-4 aggravates PolyQ-mediated neurodegeneration by modulating NF-κB mediated immune response in Drosophila
Saurabh Rai1, Madhu G Tapadia1
1Cytogenetics Laboratory, Department of Zoology, Banaras Hindu University, Varanasi, Uttar Pradesh, India.
Insights
Heat shock cognate 70-4 (Hsc70-4) protein plays a key role in Huntington
Area of Science:
- Molecular Biology
- Neuroscience
- Genetics
Background:
- Huntington's disease (HD) is a neurodegenerative disorder caused by expanded CAG repeats in the huntingtin (HTT) gene, leading to mutated huntingtin (mHtt) protein aggregation.
- Cellular homeostasis is disrupted by mHtt aggregates, which interact with essential cellular proteins.
- Heat shock proteins, including Hsp70 family members, are involved in cellular stress response and protein folding.
Purpose of the Study:
- To investigate the specific role of the heat shock cognate (Hsc70) isoform, Hsc70-4/HSPA8, in polyglutamine (PolyQ)-mediated pathogenicity.
- To explore the molecular mechanisms linking Hsc70-4 to PolyQ toxicity and cellular dysfunction in a Drosophila model.
Main Methods:
- Utilized a Drosophila model expressing PolyQ proteins to study Huntington's disease pathogenesis.
- Manipulated the expression of Hsc70-4 (HSPA8) to assess its impact on PolyQ toxicity.
- Analyzed cellular and behavioral phenotypes, including ommatidia arrangement, optic neuron integrity, phototaxis, immune response (NF-κB, antimicrobial peptides), JNK signaling, caspase activity, and protein-protein interactions.
Main Results:
- Enhanced expression of Hsc70-4 was observed under PolyQ conditions in Drosophila.
- Downregulation of Hsc70-4 significantly rescued PolyQ pathogenicity, improving visual system integrity and restoring phototaxis.
- Reduced Hsc70-4 expression attenuated the augmented immune response, normalized JNK signaling, decreased caspase activity, and rescued photoreceptor cells.
Conclusions:
- Hsc70-4/HSPA8 plays a distinct and critical role in driving PolyQ-mediated pathogenicity.
- Targeting Hsc70-4 offers a potential therapeutic strategy for mitigating Huntington's disease progression.
- Demonstrated a functional interaction between Hsc70-4, PolyQ aggregates, and NF-κB, highlighting a key molecular link in PolyQ toxicity.
Abstract:
Huntington's disease occurs when the stretch of CAG repeats in exon 1 of the huntingtin (htt) gene crosses the permissible limit, causing the mutated protein (mHtt) to form insoluble aggregates or inclusion bodies. These aggregates are non-typically associated with various essential proteins in the cells, thus disrupting cellular homeostasis. The cells try to bring back normalcy by synthesizing evolutionary conserved cellular chaperones, and Hsp70 is one of the families of heat shock proteins that has a significant part in this, which comprises of heat-inducible and cognate forms. Here, we demonstrate that the heat shock cognate (Hsc70) isoform, Hsc70-4/HSPA8, has a distinct role in polyglutamate (PolyQ)-mediated pathogenicity, and its expression is enhanced in the polyQ conditions in Drosophila. Downregulation of hsc70-4 rescues PolyQ pathogenicity with a notable improvement in the ommatidia arrangement and near-normal restoration of optic neurons leading to improvement in phototaxis response. Reduced hsc70-4 also attenuates the augmented immune response by decreasing the expression of NF-κB and the antimicrobial peptides, along with that JNK overactivation is also restored. These lead to the rescue of the photoreceptor cells, indicating a decrease in the caspase activity, thus reverting the PolyQ pathogenicity. At the molecular level, we show the interaction between Hsc70-4, Polyglutamine aggregates, and NF-κB, which may be responsible for the dysregulation of signaling molecules in polyQ conditions. Thus, the present data provides a functional link between Hsc70-4 and NF-κB under polyQ conditions.
