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  • Review Article
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Pathways to motor incoordination: the inherited ataxias

Nature Reviews Neuroscience volume 5, pages 641–655 (2004)Cite this article

Key Points

  • Humans are afflicted by two forms of hereditary ataxia, autosomal recessive and autosomal dominant. Neurological dysfunction associated with these disorders impairs motor coordination.

  • Mutated proteins associated with autosomal recessive ataxias compromise the regulation of energy output, oxidative stress, DNA maintenance and the cell cycle. Diseases of this type include Friedreich ataxia, Cayman ataxia, ataxia telangiectasia and abetalipoproteinaemia.

  • Friedreich ataxia is the most common hereditary ataxia. Mutation of the mitochondrial protein frataxin causes this disorder, probably by perturbing mitochondrial iron metabolism and the cellular response to oxidative stress.

  • The second most prevalent form of ataxia is the genomic instability syndrome ataxia telangiectasia. The gene that is mutated in this disorder, ATM, encodes a protein that coordinates cellular responses to DNA damage.

  • Autosomal dominant spinocerebellar ataxias are caused by expanded CAG-triplet repeats in the respective disease genes. The encoded mutant ataxin proteins have abnormally long polyglutamine stretches, leading to toxic gain-of-function.

  • Protein aggregates are hallmarks of neurodegeneration in the brains of patients with spinocerebellar ataxia, but a direct link between these aggregates and neuronal death has yet to be confirmed. There is evidence that perturbed gene transcription might also contribute to neurodegeneration.

Abstract

Two groups of hereditary ataxias are most relevant to humans — the autosomal recessive ataxias and the autosomal dominant spinocerebellar ataxias. Recessive ataxias are multisystem disorders that are characterized by inactivating mutations that result in loss of protein function. By contrast, cell death associated with dominant spinocerebellar ataxias is mostly restricted to the CNS, and cellular control of protein folding and processing is affected. The purpose of this review is to provide an integrated view of the field, encompassing the similarities — which are few — and the differences — which are many — between pathological processes that cause ataxia. In reviewing the current knowledge of ataxias, we discuss recent insights into the pathogenic mechanisms that lead to specific neuronal dysfunction and neurodegeneration.

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Figure 1: Pathological features of recessive ataxias.
Figure 2: Schematic model for the pathogenic mechanisms of Friedreich ataxia (FRDA).
Figure 3: DNA repair and maintenance in autosomal recessive ataxias.
Figure 4: Pathological features of dominant ataxias.
Figure 5: Proposed pathogenic mechanisms of polyglutamine-associated dominant ataxias.

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Acknowledgements

This study was promoted by the European Community (EUROSCA integrated project awarded to S.D.). Work in the authors' laboratory is supported by grants from the Italian Ministry of Health (Ministero della Salute to S.D. and F.T.), Fondazione Cariplo (F.T.) and Fondazione Pierfranco e Luisa Mariani (F.T.). We wish to thank our colleagues Cinzia Gellera and Caterina Mariotti for invaluable discussion and contribution.

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Authors and Affiliations

  1. Laboratory of Cell Pathology, IRCCS-Istituto Nazionale Neurologico Carlo Besta, via Celoria 11, Milan, 20133, Italy

    Franco Taroni

  2. Division of Biochemistry and Genetics, IRCCS-Istituto Nazionale Neurologico Carlo Besta, via Celoria 11, Milan, 20133, Italy

    Stefano DiDonato

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  1. Franco Taroni
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Correspondence to Stefano DiDonato.

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DATABASES

Entrez Gene

APTX

ATCAY

Atm1

ATM

CRX

DRPLA

FRDA

Isu1

MRE11

MTP

NBS1

Nfs1

PARP

PNKP

RAD50

Rpn10

SCA1

SCA2

SCA3

SCA6

SCA7

SCA17

SETX

TDP1

TTPA

VCP

XRCC1

Yfh1

OMIM

ABL

AT

AOA1

AOA2

ATLD

AVED

Cayman ataxia

FRDA

NBS

SCAN1

XLSA/A

FURTHER INFORMATION

DiDonato's homepage

Istituto Nazionale Neurologico Carlo Besta

Glossary

OCULOMOTOR APRAXIA

Impairment of planning and organization of voluntary conjugate movements of the eyes (saccadic movements). When asked to move the eyes laterally, the patient makes a lateral head turn, and the eyes then follow. Involuntary and random eye movements are usually normal.

FERRITINS

A class of major iron-storage proteins that are widely distributed in animals, plants and microorganisms. They consist of a mineral core of hydrated ferric oxide and a hollow spherical protein shell composed of 24 apoferritin monomers. The iron is therefore stored in a soluble, nontoxic, readily available form.

CRAL-TRIO

CRAL defines the C-terminal binding motif of various retinaldehyde/retinal-binding proteins that might be functional components of the visual cycle. TRIO refers to a protein that contains three enzyme domains: a protein kinase domain and two distinct guanine nucleotide exchange factor domains. Proteins with a CRAL-TRIO domain are transfer proteins.

DOUBLE-STRAND BREAKS

(DSBs). DNA lesions caused by agents including ionizing radiation and reactive chemicals.

SINGLE-STRAND BREAKS

(SSBs). DNA lesions that arise directly from an attack on deoxyribose by free radicals, or indirectly as, for example, normal intermediates of DNA base excision repair.

MICROCEPHALY

The condition of having an abnormally small head (circumference smaller than 2 standard deviations of the mean for age and sex). It most often occurs because of failure of the brain to grow at a normal rate. It usually results in mental retardation.

SSBR COMPLEX

A coordinated group of proteins that participate in the repair of SSBs.

ABORTIVE SSBs

Inhibition of the catalytic activity of TOPO1, which transiently breaks DNA and generates SSBs, results in an abortive TOPO1–DNA complex.

OPHTHALMOPLEGIA

Paralysis or weakness of one or more of the muscles that control eye movement, innervated by the third (oculomotor), fourth (trochlear) and sixth (abducens) cranial nerves. It results in the impairment of both voluntary and involuntary movements of the eyes.

AMYOTROPHY

Progressive wasting of muscle tissues.

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Taroni, F., DiDonato, S. Pathways to motor incoordination: the inherited ataxias. Nat Rev Neurosci 5, 641–655 (2004). https://doi.org/10.1038/nrn1474

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