Mitochondrial impairment observed in fibroblasts from South African Parkinson's disease patients with parkin mutations.
Parkinson's disease (PD), defined as a neurodegenerative disorder, is characterized by the loss of dopaminergic neurons in the substantia nigra in the midbrain. Loss-of-function mutations in the parkin gene are a major cause of autosomal recessive, early-onset PD. Parkin has been implicated in the maintenance of healthy mitochondria, although previous studies show conflicting findings regarding mitochondrial abnormalities in fibroblasts from patients harboring parkin-null mutations. The aim of the present study was to determine whether South African PD patients with parkin mutations exhibit evidence for mitochondrial dysfunction. Fibroblasts were cultured from skin biopsies obtained from three patients with homozygous parkin-null mutations, two heterozygous mutation carriers and two wild-type controls. Muscle biopsies were obtained from two of the patients. The muscle fibers showed subtle abnormalities such as slightly swollen mitochondria in focal areas of the fibers and some folding of the sarcolemma. Although no differences in the degree of mitochondrial network branching were found in the fibroblasts, ultrastructural abnormalities were observed including the presence of electron-dense vacuoles. Moreover, decreased ATP levels which are consistent with mitochondrial dysfunction were observed in the patients' fibroblasts compared to controls. Remarkably, these defects did not manifest in one patient, which may be due to possible compensatory mechanisms. These results suggest that parkin-null patients exhibit features of mitochondrial dysfunction. Involvement of mitochondria as a key role player in PD pathogenesis will have important implications for the design of new and more effective therapies.
Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. Electronic address: celiavdm@sun.ac.za.
Celia
C
van der Merwe
Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, South Africa.
Ben
B
Loos
Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
Chrisna
C
Swart
Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa; MRC Centre for Molecular and Cellular Biology and the DST/NRF Centre of Excellence for Biomedical TB Research, Stellenbosch University, Cape Town, South Africa.
Craig
C
Kinnear
Division of Neurology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
Franclo
F
Henning
Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa; Department of Statistics, University of the Western Cape, Cape Town, South Africa.
Lize
L
van der Merwe
National Health Laboratory Services (NHLS) Histopathology Laboratory, Red Cross Children's Hospital, Cape Town, South Africa.
Komala
K
Pillay
Division of Anatomical Pathology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
Nolan
N
Muller
Neuropathology Unit, Division of Anatomical Pathology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
Dan
D
Zaharie
Cell Imaging Unit, Central Analytical Facility, Stellenbosch University, Cape Town, South Africa.
Lize
L
Engelbrecht
Division of Neurology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
Jonathan
J
Carr
Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
Soraya
S
Bardien
D000255:Adenosine Triphosphate / Q000378:metabolism; D005347:Fibroblasts / Q000201:enzymology / Q000648:ultrastructure; D006801:Humans; D008928:Mitochondria / Q000201:enzymology* / Q000648:ultrastructure*; D018485:Muscle Fibers, Skeletal / Q000648:ultrastructure; D018482:Muscle, Skeletal / Q000648:ultrastructure; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology*; D012508:Sarcolemma / Q000648:ultrastructure; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
D000255:Adenosine Triphosphate; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein
Fibroblasts; Mitochondrial dysfunction; Muscle; Parkin mutations; Parkinson’s disease