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Background: Oculopharyngeal muscular dystrophy (OPMD) is caused by expansions of the poly (A) binding protein 2 ( PABP2 ) gene. Previous histological analyses have revealed mitochondrial abnormalities in the muscles of OPMD patients but their significance remains uncertain. Objective: We had the rare opportunity to study monozygotic twins with identical expansions of the PABP2 gene but with markedly different severities of OPMD. Both had histological features of mitochondrial myopathy. We determined whether mitochondrial DNA abnormalities underlay these changes. Methods: Clinical information was obtained by history and examination. Muscle biopsies were obtained from each subject and genetic analysis was performed using long-range PCR and Southern blotting. Results: We demonstrate, for the first time, the presence of mitochondrial DNA (mtDNA) deletions by Southern blotting in individuals with OPMD. This correlates with the presence of mitochondrial myopathy in both twins. Moreover, both twins had different mtDNA deletions, which might explain their phenotypic differences. Conclusion: We hypothesise that mitochondrial dysfunction may occur as a consequence of PABP2 gene mutations, and that this dysfunction may affect the phenotypic manifestations of OPMD.

Mutations in the PINK1 and Parkin genes are associated with autosomal-recessive Parkinson9s disease. PINK1 encodes a mitochondrial localized protein kinase and Parkin encodes an ubiquitin E3 ligase. Several lines of evidence indicate that the enzymes encoded by these genes function in a common signalling pathway. For example patients bearing mutations in PINK1 or Parkin share a similar phenotype. We have previously reported that PINK1 is activated by mitochondrial depolarization and stimulates Parkin activity by phosphorylating Serine 65 (Ser65) that lies within its ubiquitin-like (Ubl) domain. In a screen for novel PINK1 substrates we unexpectedly identified an ubiquitin phosphopeptide phosphorylated at Ser65. We undertook a series of biochemical experiments that provide striking evidence that Ser65-phosphorylated ubiquitin functions as a critical activator of Parkin. We also provide evidence that optimal activation of Parkin is dependent on PINK1-mediated phosphorylation of both Parkin at Ser65 and ubiquitin at Ser65. Our study defines PINK1 as the first ubiquitin kinase and suggests that small molecules that mimic Ser65-phosphorylated ubiquitin could hold promise as novel therapies for Parkinson9s.