Background: Altered splicing of parkin under cellular stress could lead to changes in gene expression and altered protein activity. The causative role of parkin in sporadic Parkinson's disease (PD) is unknown.
Objectives: We described a parkin splice variant (SV) in the substantia nigra and leukocytes of sporadic PD patients. Using a case control methodology, we investigated the exon 4 SV (E4SV) and wild-type parkin expression in the leukocytes of sporadic PD patients and healthy individuals.
Methods/results: We identified a parkin E4SV in the substantia nigra and leukocytes of sporadic PD patients and controls by reverse transcriptase-polymerase chain reaction (PCR). The exon 4 (122 bp) deletion resulted in a reading frame shift over the junction of exons 3-5 and a stop codon (tga) 17 bp downstream from exon 3. The translated truncated protein was associated with a total loss of the two-RING finger functional domain. Utilizing TaqMan real-time PCR with probes located across the junction of exons 3-4 or 3-5, we demonstrated an over-expression of E4SV/wild-type parkin ratio in the leukocytes of sporadic PD patients compared to age-, gender-, and race-matched controls (p<0.0005). A multivariate regression analysis demonstrated that the ratio of E4SV/wild-type parkin expression increased with age in PD patients, but this was not observed in the controls (p<0.0005).
Conclusion: The relative expression of E4SV/wild type parkin was increased in sporadic PD compared to healthy controls. Based on our observations, further functional studies to determine the pathophysiologic role of E4SV in sporadic PD patients will be of importance.