CMT 2A: The role of mitochondria in inherited neurodegenerative diseases

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J Neurochem. 2006 Jun;97(6):1659-75

The role of mitochondria in inherited neurodegenerative diseases.

Kwong JQ, Beal MF, Manfredi G.

Department of Neurology and Neuroscience, Weill Medical College of

Cornell University, New York, New York, USA.

In the past decade, the genetic causes underlying familial forms of

many neurodegenerative disorders, such as Huntington's disease,

Parkinson's disease, Alzheimer's disease, amyotrophic lateral

sclerosis, Friedreich ataxia, hereditary spastic paraplegia, dominant

optic atrophy, Charcot-Marie-Tooth type 2A, neuropathy ataxia and

retinitis pigmentosa, and Leber's hereditary optic atrophy have been

elucidated.

However, the common pathogenic mechanisms of neuronal death are still

largely unknown.

Recently, mitochondrial dysfunction has emerged as a

potential 'lowest common denominator' linking these disorders. In

this review, we discuss the body of evidence supporting the role of

mitochondria in the pathogenesis of hereditary neurodegenerative

diseases.

We summarize the principal features of genetic diseases caused by

abnormalities of mitochondrial proteins encoded by the mitochondrial

or the nuclear genomes. We then address genetic diseases where mutant

proteins are localized in multiple cell compartments, including

mitochondria and where mitochondrial defects are likely to be

directly caused by the mutant proteins.

Finally, we describe examples of neurodegenerative disorders where

mitochondrial dysfunction may be 'secondary' and probably concomitant

with degenerative events in other cell organelles, but may still play

an important role in the neuronal decay.

Understanding the contribution of mitochondrial dysfunction to

neurodegeneration and its pathophysiological basis will significantly

impact our ability to develop more effective therapies for

neurodegenerative diseases.