Mutations in THAP1/DYT6 reveal that diverse dystonia genes disrupt similar neuronal pathways and functions

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Dystonia is a movement disorder with diverse genetic causes.
• The specific role of THAP1 mutations in dystonia (DYT6) and downstream effects remain unclear.
• Investigating shared molecular pathways in different dystonia forms is crucial.

Purpose of the Study:

• To investigate the in vivo transcriptional effects of THAP1 mutations in neonatal mouse brain.
• To identify downstream targets and affected pathways in THAP1-associated dystonia.
• To explore potential convergence of pathogenetic mechanisms across inherited dystonia types.

Main Methods:

• RNA-sequencing (RNA-Seq) was employed to analyze gene expression in neonatal mouse striatum and cerebellum with THAP1 mutations (C54Y or ΔExon2 alleles).
• Bioinformatic analysis identified enriched pathways and gene ontology terms.
• Electrophysiological and neurite outgrowth assays were performed, with partial correction using salubrinal.

Main Results:

• THAP1 mutations dysregulated pathways including eIF2α Signaling, Mitochondrial Dysfunction, Neuron Projection Development, Axonal Guidance Signaling, and Synaptic LongTerm Depression in a genotype and tissue-dependent manner.
• Electrophysiological and neurite outgrowth assays confirmed plasticity defects.
• These affected pathways are implicated in other inherited dystonia forms, such as DYT1.

Conclusions:

• THAP1 dysfunction affects critical neuronal pathways involved in development and plasticity.
• These findings suggest a potential convergence of pathogenetic mechanisms in the pathophysiology of various inherited dystonia forms.
• Understanding these shared pathways may offer therapeutic targets for dystonia.