V363I and V363A mutated tau affect aggregation and neuronal dysfunction differently in C. elegans.

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Mutations in the microtubule-associated protein tau (MAPT) gene cause tauopathies, a group of neurodegenerative diseases.
• Two novel MAPT mutations, V363A and V363I, were identified in patients with frontotemporal lobar degeneration.

Purpose of the Study:

• To investigate how tau V363A and V363I mutations affect protein misfolding and neurodegeneration in vivo.
• To compare the in vivo effects of tau V363A and V363I with wild-type tau (tau WT).

Main Methods:

• Generated transgenic C. elegans expressing human 2N4R tau with V363A, V363I, or wild-type mutations in all neurons.
• Assessed behavioral defects, misfolding, proteotoxicity, phosphorylation, and aggregation propensity of mutated tau proteins.

Main Results:

• Pan-neuronal expression of tau WT caused neurodegenerative phenotypes in worms.
• Both tau V363A and V363I exacerbated neurodegenerative defects, leading to distinct neuronal dysfunctions and synaptic impairments.
• Tau V363A induced a pharyngeal defect, previously unlinked to tau mutations.
• Tau V363I showed increased phosphorylation and formed insoluble aggregates, while tau V363A favored soluble oligomeric assemblies.

Conclusions:

• Single amino acid substitutions in tau can distinctly alter its aggregation into soluble and insoluble forms.
• These distinct aggregation pathways may contribute to specific neuropathological phenotypes in tauopathies.
• The findings offer new insights into the pathogenic mechanisms underlying tauopathies.