The centrosome in human genetic disease

Key Points

  • Historically, the centrosome has been linked to cell-cycle control and its role in cancer has been studied extensively. More recent evidence has shown, however, that the centrosome is also involved in several cellular processes, including protein degradation, cell migration and axonal growth.

  • Ubiquitin-proteasome degradation is crucial for the regulation of a number of cellular processes, and the centrosome seems to be a cellular location in which the proteasome machinery, as well as target proteins, accumulate. This spatial association seems to be important at the functional level, as dissociation of the proteasome from the centrosome impedes ubiquitin-proteasome degradation.

  • Defects in protein clearance have been implicated in neurodegenerative diseases such as Parkinson disease. As such, centrosomal dysfunction might have a direct or indirect role in the pathogenesis of this type of human disorders.

  • The centrosome also has a crucial role in cell migration, as exemplified by the defects in neuronal migration that are due to defects in several centrosomal or centrosome-associated proteins.

  • The cytoskeletal organizing capabilities of the centrosome are required not only for axonal growth but also for axonal maintenance; defects in the centrosome-associated protein spastin lead to axonal degeneration in hereditary spastic paraplegia.

  • Defective microtubule-dependent vesicular transport is likely to underlie the pathogenesis of Huntington disease and centrosomal function might be relevant to disease onset and progression.

  • The link between cilia, the centrosome and the structurally and biochemically related basal body are highlighted by recent findings on Bardet–Biedl syndrome; defects in these structures lead to a number of human disorders that range from the development of cystic kidneys to perturbed left–right symmetry.

Abstract

The centrosome is an indispensable component of the cell-cycle machinery of eukaryotic cells, and the perturbation of core centrosomal or centrosome-associated proteins is linked to cell-cycle misregulation and cancer. Recent work has expanded our understanding of the functional complexity and importance of this organelle. The centrosomal localization of proteins that are involved in human genetic disease, and the identification of novel centrosome-associated proteins, has shown that numerous, seemingly unrelated, cellular processes can be perturbed by centrosomal dysfunction. Here, we review the mechanistic relationship between human disease phenotypes and the function of the centrosome, and describe some of the newly-appreciated functions of this organelle in animal cells.

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Figure 1: Schematic representation of the centrosome.
Figure 2: Ubiquitin-mediated protein degradation is concentrated at the centrosome.
Figure 3: The centrosome in cell migration.
Figure 4: Potential functional links between the cilia and the cell interior.

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Acknowledgements

There has been a huge amount of data from laboratories around the world on the biochemical, cellular and genetic properties of the centrosome and we apologize to colleagues whose work we were unable to represent owing to space constraints. We thank P. Beales, M. Leroux and the members of the Katsanis laboratory for their critical evaluation of the manuscript. This work was supported in part by a National Institute of Child Health and Development, National Institutes of Health grant to N.K.

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Correspondence to Nicholas Katsanis.

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DATABASES

Entrez

LIS1

DCX

NDE1

NDEL1

DISC1

HD

HAP1

HIP1

BBS4

BBS8

BBS3

PKD1

PKD2

OMIM

Alstrom syndrome

oro-facial digital syndrome

Parkinson disease

autosomal recessive juvenile parkinsonism

lissencephaly

Miller–Dieker syndrome

schizophrenia

Huntington disease

Bardet–Biedl syndrome

Cohen syndrome

Meckel–Gruber syndrome

FURTHER INFORMATION

Katsanis laboratory

Glossary

CHROMOSOME INSTABILITY

The increased probability of acquiring chromosomal aberrations owing to defects in processes such as DNA repair, replication or chromosome segregation.

BASAL BODY

The structure found at the base of eukaryotic cilia and flagella that consists of an array of nine microtubule triplets, as well as other proteins, and which is involved in the organization and assembly of the ciliary axoneme.

ALSTROM SYNDROME

A human disorder that is characterized by retinitis pigmentosa, obesity, diabetes mellitus and perceptive deafness.

ORO-FACIAL-DIGITAL SYNDROME

An X-linked dominant condition, which is lethal in males, that is characterized by oral cavity, face and digit malformations and is often associated with brain defects and polycystic kidneys.

CILIATION

The assembly of cilia.

PROTEASOME

A cytosolic protein complex that degrades proteins that have been marked for destruction by the ubiquitination pathway.

α-SYNUCLEIN

A principal component of the proteinaceous inclusions — termed Lewy bodies — which are characteristic of certain neurodegenerative disorders such as Parkinson disease.

GLIA

The connective tissue of the central nervous system that consists of astrocytes, oligodendrocytes and microglia.

PSEUDOPOD

The transient extension of the cell membrane that is used for locomotion or feeding in some microorganisms.

HETEROTOPIA

An abnormal localization of cells or organs.

DYNEIN

A microtubule-dependent motor protein that is involved in several processes which, in the case of cytoplasmic dynein, includes organelle transport and mitosis, and in the case of ciliary dynein, provides the force for the movement of cilia and flagella.

MICROTUBULE CATASTROPHE

A switch from growth to the rapid shortening of microtubule fibres, which is due to increased depolimerization of tubulin monomers.

SCHIZOPHRENIA

A mental disorder that is characterized by, among other disturbances, the separation between emotions and thought processes, delusions and hallucinations, mood perturbations and autistic behaviour.

CORTICOSPINAL TRACTS

A bundle of nerve fibres that directly link the cerebral cortex to the spinal cord.

AAA FAMILY

A protein family with members that share a conserved region of approximately 220 amino-acid residues that contains an ATP-binding site. AAA stands for 'ATPases associated with diverse cellular activities'.

HeLa CELLS

A human cell line that is derived from the cervical carcinoma of Henrietta Lacks.

STRIATUM

The region of the brain that receives both input and output signals from the cortex and controls complex motor activity.

ANEUPLOIDY

Presence of an abnormal number of chromosomes. For example, in the case of trisomies, an extra copy of a chromosome is present.

MIDBODY

The cytoplasmic bridge that links daughter cells at the end of cytokinesis.

HYDROCEPHALUS

A condition that is characterized by the abnormal accumulation of cerebrospinal fluid in the ventricles of the brain, which lead to elevated intracranial pressure that causes the skull bones to expand and results in an enlargement of the head.

SITUS INVERSUS

Reversal of the left–right body axis of symmetry owing to the failure to align left–right with respect to the antero-posterior and dorso-ventral axes.

POLYDACTYLY

A congenital defect that is characterized by the presence of extra digits.

PERICENTRIOLAR SATELLITES

These are electron-dense structures that associate peripherally with the chromosome.

COHEN SYNDROME

A rare autosomal-recessive human disorder that is characterized by psychomotor retardation, microcephaly, characteristic facial features, retinal dystrophy and myopia, among other phenotypic features.

MECKEL–GRUBER SYNDROME

A syndrome that is characterized by cleft palate, polydactyly and polycystic kidneys, as well as anomalies of the central nervous system, including occipital encephalocele and microcephaly.

COCHLEA

The spiral-shaped structure in the middle ear that contains the hair cells responsible for sensing sound to produce the hearing signals that are sent to the brain.

NINEIN

A centrosomal protein that is required for the microtubule organizing activity of the centrosome.

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Badano, J., Teslovich, T. & Katsanis, N. The centrosome in human genetic disease. Nat Rev Genet 6, 194–205 (2005). https://doi.org/10.1038/nrg1557

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