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Title: Mitochondrial impairment observed in fibroblasts from South African Parkinson’s disease patients with parkin mutations

Highlights: • Mitochondrial dysfunction observed in patients with parkin-null mutations. • Mitochondrial ATP levels were decreased. • Electron-dense vacuoles were observed in the patients. • Mitochondria from muscle biopsies appeared within normal limits. • One patient did not show these defects possibly due to compensatory mechanisms. - Abstract: 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 foundmore » 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.« less
Authors:
 [1] ;  [2] ;  [1] ;  [1] ;  [3] ;  [4] ;  [1] ;  [3] ;  [5] ;  [6] ;  [7] ;  [8] ;  [4] ;
  1. Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town (South Africa)
  2. Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch (South Africa)
  3. (South Africa)
  4. Division of Neurology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town (South Africa)
  5. National Health Laboratory Services (NHLS) Histopathology Laboratory, Red Cross Children’s Hospital, Cape Town (South Africa)
  6. Division of Anatomical Pathology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town (South Africa)
  7. Neuropathology Unit, Division of Anatomical Pathology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town (South Africa)
  8. Cell Imaging Unit, Central Analytical Facility, Stellenbosch University, Cape Town (South Africa)
Publication Date:
OSTI Identifier:
22416416
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 447; Journal Issue: 2; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ATP; BIOPSY; ELECTRONS; FIBROBLASTS; GENES; MITOCHONDRIA; MUSCLES; MUTATIONS; NERVE CELLS; NERVOUS SYSTEM DISEASES; PATHOGENESIS; PATIENTS; SKIN; THERAPY