Background: Amyotrophic lateral sclerosis (ALS) is a major cause of neurological disability and its pathogenesis remains elusive despite a multitude of studies. Although defects of the mitochondrial respiratory chain have been described in several ALS patients, their pathogenic significance is unclear. Objective: To review systematically the muscle biopsy specimens from patients with typical sporadic ALS to search for possible mitochondrial oxidative impairment. Design: Retrospective histochemical, biochemical, and molecular studies of muscle specimens. Setting: Tertiary care university. Subjects: Fifty patients with typical sporadic ALS (mean age, 55 years). Main Outcome Measure: Number of patients showing a clear muscle mitochondrial dysfunction assessed through histochemical and biochemical muscle analysis. Results: Histochemical data showed cytochrome c oxidase (COX)-negative fibers in 46% patients. Based on COX histochemical activity, patients fell into 4 groups: 27 had normal COX activity; and 8 had mild (2-4 COX-negative fibers of 100 fibers), 8 had moderate (5-10 COX-negative fibers of 100), and 7 had severe (>10 COX-negative fibers of 100) COX deficiency. Spectrophotometric measurement of respiratory chain activities showed that 3 patients with severe histochemical COX deficiency also showed combined enzyme defects. In 1 patient, COX deficiency worsened in a second biopsy taken 9 months after the first. Among the patients with severe COX deficiency, one had a new mutation in the SOD1 gene, another a mutation in the TARDBP gene, and a third patient with biochemically confirmed COX deficiency had multiple mitochondrial DNA deletions detectable by Southern blot analysis. Conclusions: Our data confirm that the histochemical finding of COX-negative fibers is common in skeletal muscle from patients with sporadic ALS. We did not find a correlation between severity of the oxidative defect and age of the patients or duration of the disease. However, the only patient who underwent a second muscle biopsy did show a correlation between severity of symptoms and worsening of the respiratory chain defect. In 7 patients, the oxidative defect was severe enough to support the hypothesis that mitochondrial dysfunction must play a role in the pathogenesis of the disease.
Mitochondrial respiratory chain dysfunction in muscle from patients with Amyotrophic Lateral Sclerosis / V. Crugnola, C. Lamperti, V. Lucchini, D. Ronchi, L. Peverelli, A. Prelle, M. Sciacco, A. Bordoni, E. Fassone, F.R. Fortunato, S.P. Corti, V. Silani, N. Bresolin, S.I. Di Mauro, G.P. Comi, M. Moggio. - In: ARCHIVES OF NEUROLOGY. - ISSN 0003-9942. - 67:7(2010 Jul), pp. 849-854.
|Titolo:||Mitochondrial respiratory chain dysfunction in muscle from patients with Amyotrophic Lateral Sclerosis|
CRUGNOLA, VERONICA (Primo)
LAMPERTI, COSTANZA (Secondo)
COMI, GIACOMO PIETRO (Penultimo)
|Parole Chiave:||motor-neuron disease; superoxide-dismutase gene; spinal muscular-atrophy; skeletal-muscle; oxidative stress; ALS patients; mutations; protein; DNA; ultrastructure|
|Settore Scientifico Disciplinare:||Settore MED/26 - Neurologia|
Settore BIO/12 - Biochimica Clinica e Biologia Molecolare Clinica
|Data di pubblicazione:||lug-2010|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1001/archneurol.2010.128|
|Appare nelle tipologie:||01 - Articolo su periodico|