Are interrupted SCA2 CAG repeat expansions responsible for parkinsonism?

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Autosomal dominant parkinsonism (ADP) is frequently caused by LRRK2 mutations (e.g., G2019S) or genes linked to autosomal dominant cerebellar ataxia (ADCA), such as SCA2.
• SCA2 gene mutations, specifically CAG/CAA repeat expansions, are implicated in both ADCA and, less commonly, ADP.

Purpose of the Study:

• To investigate the role of SCA2 repeat expansions and LRRK2 mutations in families with autosomal dominant parkinsonism (ADP).
• To compare the clinical phenotypes associated with different SCA2 repeat expansion configurations and LRRK2 mutations.

Main Methods:

• Screened 164 families with ADP for SCA2, SCA3, and SCA17 gene expansions and LRRK2 G2019S mutation.
• Sequenced SCA2 CAG/CAA repeat expansions to determine their structure (interrupted vs. uninterrupted).
• Compared phenotypes of patients with ADP due to SCA2, LRRK2, or unknown mutations, and SCA2 patients with interrupted vs. uninterrupted expansions.

Main Results:

• Identified SCA2 repeat expansions (37-39 repeats, interrupted, stable) in three French ADP families.
• Patients with interrupted SCA2 expansions presented with levodopa-responsive parkinsonism, symmetric signs, and less rigidity compared to LRRK2-related parkinsonism.
• Uninterrupted, similar-sized SCA2 repeats were associated with ADCA, with cerebellar ataxia as the primary symptom.

Conclusions:

• The configuration of SCA2 CAG/CAA repeat expansions is critical in determining phenotype variability between ADP and ADCA.
• Interrupted SCA2 expansions in ADP may involve different pathogenic mechanisms than uninterrupted expansions causing ADCA.
• Interruption of SCA2 repeat expansions modifies characteristics associated with uninterrupted repeats, such as somatic mosaicism and hairpin RNA formation.