DNAJB6, a Key Factor in Neuronal Sensitivity to Amyloidogenesis
Arun Thiruvalluvan1, Eduardo P de Mattos1, Jeanette F Brunsting1
1Department of Biomedical Sciences of Cells & Systems, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
Abstract:
CAG-repeat expansions in at least eight different genes cause neurodegeneration. The length of the extended polyglutamine stretches in the corresponding proteins is proportionally related to their aggregation propensity. Although these proteins are ubiquitously expressed, they predominantly cause toxicity to neurons. To understand this neuronal hypersensitivity, we generated induced pluripotent stem cell (iPSC) lines of spinocerebellar ataxia type 3 and Huntington's disease patients. iPSC generation and neuronal differentiation are unaffected by polyglutamine proteins and show no spontaneous aggregate formation. However, upon glutamate treatment, aggregates form in neurons but not in patient-derived neural progenitors. During differentiation, the chaperone network is drastically rewired, including loss of expression of the anti-amyloidogenic chaperone DNAJB6. Upregulation of DNAJB6 in neurons antagonizes glutamate-induced aggregation, while knockdown of DNAJB6 in progenitors results in spontaneous polyglutamine aggregation. Loss of DNAJB6 expression upon differentiation is confirmed in vivo, explaining why stem cells are intrinsically protected against amyloidogenesis and protein aggregates are dominantly present in neurons.
Insights
Polyglutamine diseases like spinocerebellar ataxia and Huntington's disease show neuronal hypersensitivity. Stem cells are protected from protein aggregates due to chaperone DNAJB6 expression, which is lost during neuronal differentiation.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- CAG-repeat expansions in genes lead to neurodegenerative diseases.
- Polyglutamine proteins aggregate, causing neuronal toxicity despite ubiquitous expression.
Purpose of the Study:
- Investigate neuronal hypersensitivity to polyglutamine proteins.
- Understand the protective mechanisms in stem cells versus neurons.
Main Methods:
- Generated induced pluripotent stem cell (iPSC) lines from spinocerebellar ataxia type 3 and Huntington's disease patients.
- Differentiated iPSCs into neurons and neural progenitors.
- Analyzed protein aggregation and chaperone expression (DNAJB6) under glutamate treatment.
Main Results:
- iPSCs and neural progenitors did not form spontaneous aggregates.
- Glutamate treatment induced aggregation in neurons but not progenitors.
- Chaperone network rewiring occurred during differentiation, including loss of DNAJB6 expression.
- DNAJB6 upregulation in neurons reduced aggregation; its knockdown in progenitors caused aggregation.
Conclusions:
- Stem cells are intrinsically protected against polyglutamine aggregation.
- Loss of DNAJB6 expression during neuronal differentiation explains neuronal hypersensitivity.
- DNAJB6 plays a critical role in preventing polyglutamine-induced protein aggregation in neurons.
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