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P301 L, an FTDP-17 Mutant, Exhibits Enhanced Glycation in vitro
Shweta Kishor Sonawane1,2, Subashchandrabose Chinnathambi1,2
1Neurobiology Group, Biochemical Sciences Division, CSIR-National Chemical Laboratory, Pune, India.
Background:
Frontotemporal dementia and parkinsonism-linked to chromosome-17 are a group of diseases with tau mutations leading to primary tauopathies which include progressive supranuclear palsy, corticobasal syndrome, and frontotemporal lobar degeneration. Alzheimer's disease is a non-primary tauopathy, which displays tau neuropathology of excess tangle formation and accumulation. FTDP-17 mutations are responsible for early onset of AD, which can be attributed to compromised physiological functions due to the mutations. Tau is a microtubule-binding protein that secures the integrity of polymerized microtubules in neuronal cells. It malfunctions owing to various insults and stress conditions-like mutations and post-translational modifications.
Objective:
In this study, we modified the wild type and tau mutants by methyl glyoxal and thus studied whether glycation can enhance the aggregation of predisposed mutant tau.
Methods:
Tau glycation was studied by fluorescence assays, SDS-PAGE analysis, conformational evaluation, and transmission electron microscopy.
Results:
Our study suggests that FTDP-17 mutant P301 L leads to enhanced glycation-induced aggregation as well as advanced glycation end products formation. Glycation forms amorphous aggregates of tau and its mutants without altering its native conformation.
Conclusion:
The metabolic anomalies and genetic predisposition have found to accelerate tau-mediated neurodegeneration and prove detrimental for the early-onset of Alzheimer's disease.
Insights
Glycation enhances the aggregation of tau mutations linked to frontotemporal dementia and parkinsonism-linked to chromosome-17 (FTDP-17), accelerating neurodegeneration and early-onset Alzheimer's disease.
Area of Science:
- Neuroscience
- Biochemistry
- Genetics
Background:
- Frontotemporal dementia and parkinsonism-linked to chromosome-17 (FTDP-17) are primary tauopathies caused by tau mutations.
- Alzheimer's disease (AD) involves tau neuropathology, and FTDP-17 mutations can trigger early-onset AD.
- Tau protein is crucial for microtubule integrity in neurons but can malfunction due to mutations and stress.
Purpose of the Study:
- To investigate if glycation by methyl glyoxal enhances tau aggregation in wild-type and FTDP-17 mutant tau.
- To understand the impact of glycation on tau conformation and aggregate formation.
Main Methods:
- Tau proteins (wild-type and FTDP-17 mutants) were modified using methyl glyoxal.
- Glycation and aggregation were analyzed using fluorescence assays, SDS-PAGE, conformational evaluation, and transmission electron microscopy.
Main Results:
- FTDP-17 mutant P301L exhibited enhanced glycation-induced aggregation and advanced glycation end product formation.
- Glycation led to the formation of amorphous tau aggregates without altering native protein conformation.
Conclusions:
- Metabolic anomalies and genetic predisposition accelerate tau-mediated neurodegeneration.
- Glycation of tau, particularly in FTDP-17 mutants, contributes to neurodegenerative processes and early-onset Alzheimer's disease.
