The completion of the Human Genome Project aroused renewed interest in alternative splicing, an efficient and
widespread mechanism that generates multiple protein isoforms from individual genes. Although our knowledge about alternative
splicing is growing exponentially, its real impact on cellular life is still to be clarified. Connecting all splicing
features (genes, splice transcripts, isoforms, and relative functions) may be useful to resolve this tangle. Herein, we will
start from the case of a single gene, Parkinson protein 2, E3 ubiquitin protein ligase (PARK2), one of the largest in our genome.
This gene is implicated in the pathogenesis of autosomal recessive juvenile Parkinsonism and it has been recently
linked to cancer, leprosy, autism, type 2 diabetes mellitus and Alzheimer’s disease. PARK2 primary transcript undergoes
an extensive alternative splicing, which enhances transcriptomic diversification and protein diversity in tissues and cells.
This review will provide an update of all human PARK2 alternative splice transcripts and isoforms presently known, and
correlate them to those in rat and mouse, two common animal models for studying human disease genes. Alternative
splicing relies upon a complex process that could be easily altered by both cis and trans-acting mutations. Although the
contribution of PARK2 splicing in human disease remains to be fully explored, some evidences show disruption of this
versatile form of genetic regulation may have pathological consequences.