Ž.
Biochimica et Biophysica Acta 1364 1998 261–270
Human complex I defects in neurodegenerative diseases
A.H.V. Schapira
)
UniÕersity Department of Clinical Neurosciences, Royal Free Hospital School of Medicine, Rowland Hill Street, London NW3 2PF, UK
UniÕersity Department of Clinical Neurology, Institute of Neurology, London, UK
Received 22 January 1998; accepted 29 January 1998
Abstract
Complex I deficiency, either specific or associated with other respiratory chain defects, has been identified in
myopathies, encephalomyopathies and in three ‘neurodegenerative’ disorders: Parkinson’s disease, dystonia and Leber’s
hereditary optic neuropathy. The complex I defect is expressed in blood in all these three but, to date, only in LHON have
specific mitochondrial DNA mutations been identified. Recent work with r8 cybrids indicates that, in a subgroup of patients
at least, the complex I deficiency is determined by mtDNA, in contrast to dystonia where a nuclear gene defect or toxic
influence appears a more likely cause. The actions of specific toxins, e.g., MPTP continue to play an important role in our
understanding of pathogenesis of neurodegeneration, particularly in PD. q1998 Elsevier Science B.V.
Keywords: Parkinson’s disease; Complex I; Mitochondrion; mtDNA; Dystonia; Leber’s hereditary optic neuropathy
1. Introduction
Ž.
NADH ubiquinone reductase complex I is the
first enzyme protein complex of the mitochondrial
respiratory chain. Details of the structure and func-
tion of complex I will be described elsewhere in this
issue, and this review will focus on neurodegenera-
tive disorders associated with complex I deficiency.
Complex I comprises 41 subunits of which seven
Ž.
ND1, ND2, ND3, ND4, ND4L, ND5 and ND6 are
Ž.
encoded by mitochondrial DNA mtDNA . Numerous
mutations of mtDNA have now been associated with
wx
human disease 1 . In the majority of cases, mutations
result in a demonstrable defect of respiratory chain
)
Corresponding author. Fax: q44-171-431-1577; E-mail:
schapira@rfhsm.ac.uk
activity. Multiple respiratory chain deficiencies, e.g.,
decreased activity of complex I and complex IV, are
seen more frequently than isolated defects. This is
because the majority of mtDNA mutations involve
Ž.
transfer RNAs tRNA , abnormal functioning of
which will inevitably affect those polypeptides with
the relevant constituent amino acid. However, three
neurodegenerative diseases are associated with iso-
lated or predominant complex I deficiency: Parkin-
Ž.
son’s disease PD , focal dystonia and Leber’s heredi-
Ž.
tary optic neuropathy LHON .
2. Parkinson’s disease
PD is characterised clinically by bradykinesia,
rigidity and tremor. Onset is usually in the sixth or
seventh decades of life and lifetime risk is estimated
at 1 in 40. Pathologically, there is severe degenera-
0005-2728r98r$19.00 q 1998 Elsevier Science B.V. All rights reserved.
Ž.
PII S0005-2728 98 00032-2