Hereditary spastic paraplegias: membrane traffic and the motor pathway

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  • An Erratum to this article was published on 20 January 2011

Abstract

Voluntary movement is a fundamental way in which animals respond to, and interact with, their environment. In mammals, the main CNS pathway controlling voluntary movement is the corticospinal tract, which encompasses connections between the cerebral motor cortex and the spinal cord. Hereditary spastic paraplegias (HSPs) are a group of genetic disorders that lead to a length-dependent, distal axonopathy of fibres of the corticospinal tract, causing lower limb spasticity and weakness. Recent work aimed at elucidating the molecular cell biology underlying the HSPs has revealed the importance of basic cellular processes — especially membrane trafficking and organelle morphogenesis and distribution — in axonal maintenance and degeneration.

Key Points

  • The hereditary spastic paraplegias (HSPs) are genetic conditions in which spasticity of the legs is caused by degeneration or abnormal development of the distal ends of the corticospinal tract's longest axons.

  • Mutations in many different genes can cause HSPs. The proteins encoded by these genes seem to fall into a few functional groups, and there are multiple examples of direct interactions among proteins associated with HSPs.

  • An important group of proteins encoded by HSP genes are involved in membrane trafficking and organelle morphogenesis. This group includes three proteins — spastin, atlastin-1 and receptor expression-enhancing protein 1 (REEP1) — that are involved in membrane shaping at the tubular endoplasmic reticulum.

  • Strumpellin is also part of a complex that is involved in membrane shaping, but at endosomes — where this complex interacts with the actin cytoskeleton and is thought to be required for fission of endosomal transport tubules.

  • At least three members of the membrane traffic group of proteins associated with HSP are also implicated in bone morphogenetic protein (BMP) signalling. The best characterized of these is non imprinted in Prader-Willi/Angelman syndrome 1 (NIPA1) and its Drosophila melanogaster homologue, spichthyin, which regulates the endosomal trafficking and degradation of BMP receptors.

  • Study of the HSPs is providing insights into the basic cellular pathways that are required for axonal maintenance and that are involved in axonal degeneration. This provides the foundation for future work aimed at producing rationally designed therapies that are built on a thorough knowledge of the molecular and cellular pathology of distal axonal degeneration in HSPs.

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Figure 1: Spastin domain structure and interacting proteins.
Figure 2: The spastin–Atlastin–REEP–Reticulon complex at the ER.
Figure 3: The strumpellin–WASH complex.
Figure 4: Model of NIPA1 action on bone morphogenetic protein receptor type-2 (BMPRII) traffic.

Change history

  • 17 December 2010

    On page 37 of the above article, in Figure 3a, the protein structure labelled VPS35C was incorrectly labelled VPS39C. This has been corrected in the online version.

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Acknowledgements

We are grateful to the members of our laboratories who have contributed to HSP-related work, and to the many HSP family members who have helped with our research. We thank T. Wahlig and H. Wahlig for their tireless work in promoting interactions among HSP researchers, clinicians and families. E.R. is a Wellcome Trust Senior Research Fellow in Clinical Science (grant 082381) and is also supported by the UK Medical Research Council, the Tom Wahlig Stiftung and the UK HSP Support Group. The work of C.J.O'K. on HSP is funded by Wellcome Trust (grant WT081386). C.B. is supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, US National Institutes of Health.

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Correspondence to Evan Reid.

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Craig Blackstone's homepage

Cahir J. O'Kane's homepage

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Glossary

Upper motor neurons

Neurons whose fibres comprise descending pathways in the CNS and that are involved in voluntary control of skeletal muscle contraction. Corticospinal neurons are a type of upper motor neuron.

Decussate

To cross the midline to reach the contralateral side of the nervous system.

Paraplegia

Muscle weakness involving both legs.

Spasticity

Increased muscle tone and deep tendon reflexes resulting from damage to the corticospinal tract.

Protomer

A structural unit of an oligomeric protein.

Early secretory pathway

A pathway through the endoplasmic reticulum (ER), ER-to-Golgi intermediate compartment and the cis-Golgi apparatus.

Viral budding

The process by which an enveloped virus particle is released from the plasma membrane of a host cell.

Abscission

The final stage of cytokinesis, when the midbody connecting two daughter cells is broken and sealed.

Cytokinesis

The stage in cell division when the cytoplasm of a single cell is divided to form two daughter cells.

Midbody

The tubular plasma membrane-bound structure that connects two daughter cells in the late stage of cytokinesis.

Anti-parallel

Running side-by-side, but in opposite directions. A bundle of microtubules is anti-parallel if the microtubules of which it is comprised have plus ends facing both directions.

Paralogues

Similar DNA and protein sequences (often distinct genes) within a species.

Hydrophobic wedging

A mechanism for inducing membrane curvature by partitioning the bulk of a hydrophobic domain within the outer leaflet of the bilayer.

Tubular transport intermediates

Membrane-bound, small, cigar-shaped organelles that are trafficked from one intracellular membrane compartment to another. They are distinguished by their shape from vesicular transport intermediates, which are spherical.

Polytopic integral membrane protein

A protein that spans the membrane more than once because it has more than one transmembrane domain.

Clathrin-mediated endocytosis

The major endocytic pathway, in which cells internalize extracellular or plasma membrane molecules into clathrin-coated vesicles. Once uncoated, the vesicles are capable of fusing with internal organelles, such as endosomes.

Unfolded protein response

A cellular stress response that is triggered by excess of unfolded or misfolded proteins in the endoplasmic reticulum.

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