Molecular characterisation of SGCE-associated myoclonus-dystonia ...

Discussion 77
4.3 Parkinson’s disease: Mitochondrial function and morphology in patients
with PINK1 mutations
To date, studies investigating functional consequences of mutations in PINK1 were mostly
performed in expression cell models, animal models or for very small groups of PD patients.
Here, four siblings (from Family W, see 2.1.2.1 and Fig 4 for details) with the homozygous
PINK1 p.Q456X nonsense mutation were examined and compared to a group of eight
controls, three of whom were relatives of the affected cases. A PINK1 p.V170G missense
sample was also included in the approach.
4.3.1 Mutations in PINK1 alter respiratory chain enzyme activities
Several research groups have recently demonstrated a link between the electron transport
chain and PD (Hoepken et al., 2007; Parker et al., 1989; Piccoli et al., 2008). In Drosophila
melanogaster a PINK1 knock-down was reported to cause mitochondrial dysfunction (Park et
al., 2006). The NMD initiating mutation p.Q456X in PINK1 may also lead to loss of function
in the homozygous members of Family W. However, the activities of the respiratory chain
enzymes in fibroblasts of such nonsense mutants were not different from those in controls.
This finding is analogous to results from Piccoli et al. (2008). The authors showed that
fibroblasts with the homozygous p.W347X nonsense mutation have unaltered activities of
complex I, III and IV when measured spectrophotometrically. Why PINK1 haploinsuffiency
does not result in a detectable impairment of the respiratory chain function in PD patients
remains elusive.
In contrast, for the p.V170G missense mutant fibroblasts complex I activity was low, although
not significantly reduced. Decreased complex I activity is a common feature of several
different forms of parkinsonism. NADH dehydrogenase deficiency has been discovered in the
substantia nigra, platelets and fibroblasts of PD patients (Haas et al., 1995; Hoepken et al.,
2007; Janetzky et al., 1994; Krige et al., 1992; Mann et al., 1994; Schapira et al., 1990b).
Lacking significance of the complex I data presented here might be due to variations in the
control values, a phenomenon which was observed earlier (Williams et al., 2001). However,
reduced complex I activity was not present in all patients with PD in a study investigating
lymphocyte mitochondria (Martin et al., 1996).
For the combined measurement of complexes II and III, the missense mutant showed elevated
activity. If there was indeed an inhibition of complex I in the p.V170G mutant, hyperactivity
of complexes II and III could be interpreted as a compensatory mechanism to maintain