DCTN1 p.K56R in progressive supranuclear palsy

Area of Science:

• Neurogenetics
• Molecular Biology
• Neurology

Background:

• Mutations in dynactin DCTN1 (p150(glued)) are linked to familial motor neuron disease and Perry syndrome.
• Perry syndrome involves depression, parkinsonism, and hypoventilation.

Purpose of the Study:

• To investigate the role of DCTN1 variants in parkinsonism.
• To identify novel genetic factors contributing to Parkinson's disease and Parkinson-plus syndromes.

Main Methods:

• Sequencing of DCTN1 in Caucasian parkinsonism patients and controls.
• Genotyping of rare variants in Caucasian and Asian cohorts.
• Functional assessment of identified pathogenic variants.

Main Results:

• Seventeen rare DCTN1 variants were identified, with nine found exclusively in cases.
• The DCTN1 p.K56R variant was present in two progressive supranuclear palsy (PSP) patients with shared parkinsonism symptoms.
• In vitro studies showed DCTN1 p.K56R alters p150(glued) affinity to microtubules and cytoplasmic distribution.

Conclusions:

• The DCTN1 p.K56R variant is associated with progressive supranuclear palsy (PSP).
• This variant affects a conserved amino acid near the N-terminal 'CAP-Gly' domain.
• The identified variant alters protein function, suggesting a role in neurodegenerative disease pathogenesis.