Alternative splicing generates different parkin protein isoforms: evidences in human, rat, and mouse brain

Abstract

Parkinson protein 2, E3 ubiquitin protein ligase (PARK2) gene mutations are the most frequent causes of autosomal recessive early onset Parkinson's disease and juvenile Parkinson disease. Parkin deficiency has also been linked to other human pathologies, for example, sporadic Parkinson disease, Alzheimer disease, autism, and cancer. PARK2 primary transcript undergoes an extensive alternative splicing, which enhances transcriptomic diversification. To date several PARK2 splice variants have been identified; however, the expression and distribution of parkin isoforms have not been deeply investigated yet. Here, the currently known PARK2 gene transcripts and relative predicted encoded proteins in human, rat, and mouse are reviewed. By analyzing the literature, we highlight the existing data showing the presence of multiple parkin isoforms in the brain. Their expression emerges from conflicting results regarding the electrophoretic mobility of the protein, but it is also assumed from discrepant observations on the cellular and tissue distribution of parkin. Although the characterization of each predicted isoforms is complex, since they often diverge only for few amino acids, analysis of their expression patterns in the brain might account for the different pathogenetic effects linked to PARK2 gene mutations.

Figure 1

Chromosomal localization, exonic structure of alternative splice variants, and corresponding predicted protein isoforms of human PARK2. (a) Cytogenetic location of human PARK2 gene (6q26). (b) Exon organization map of the 21 human PARK2 splice variants currently known. Exons are represented as red bars. The size of introns (black line) is proportional to their length. The codes on left refer to gene identifiers reported in Table 1. (c) Predicted molecular architecture of PARK2 isoforms. Red boxes represent UBQ domain and blue boxes represent IBR domains.

Figure 2

Chromosomal localization, exonic structure of alternative splice variants, and corresponding predicted protein isoforms of rat PARK2. (a) Cytogenetic location of rat PARK2 gene (1q11). (b) Exon organization map of the 20 rat PARK2 splice variants currently known. Exons are represented as red bars. The size of introns (black line) is proportional to their length. The codes on left refer to gene identifiers reported in Table 2. (c) Predicted molecular architecture of PARK2 isoforms. Red boxes represent UBQ domain and blue boxes represent IBR domains.

Figure 3

Chromosomal localization, exonic structure of alternative splice variants, and corresponding predicted protein isoforms of mouse PARK2. (a) Cytogenetic location of mouse PARK2 gene (A3.2-A3.3). (b) Exon organization map of the 9 mouse PARK2 splice variants currently known. Exons are represented as red bars. The size of introns (black line) is proportional to their length. The codes on left refer to gene identifiers reported in Table 3. (c) Predicted molecular architecture of PARK2 isoforms. Red boxes represent UBQ domain and blue boxes represent IBR domains.

Figure 4

Differential detection of parkin isoforms in rat brain using five anti-parkin antibodies. (a) Representative immunoblot of parkin isoforms in rat brain visualized by using five different antibodies. Ab1, Ab2, Ab3, Ab4, and Ab5 correspond to groups #3, #4, #5, #8, and #9 of Table 5. Immunoblot for β-tubulin was used as loading control. (b) Canonical parkin sequence domains recognized by the five antibodies.