More answers, but also more questions
On top of the well-known role of mutated spastins in the lowering of microtubule-severing activity, at least one form of mutated spastin, known as M1, has been shown in rat studies to be neurotoxic when microtubule-severing activity is normal.
Additionally, some SPAST mutations occur as large deletions, which can affect the function of adjacent genes, further complicating the picture of how HSP happens.
Mutations in more than 70 distinct loci and more than 50 mutated gene products have been identified in patients with hereditary spastic paraplegias, a diverse group of neurological disorders characterized predominantly, but not exclusively, by progressive lower limb spasticity and weakness resulting from distal degeneration of corticospinal tract axons.
Mutations in the SPAST (previously known as SPG4) gene that encodes the microtubule-severing protein called spastin, are the most common cause of the disease. The aetiology of the disease is poorly understood, but partial loss of microtubule-severing activity resulting from inactivating mutations in one SPAST allele is the most postulated explanation. Microtubule severing is important for regulating various aspects of the microtubule array, including microtubule number, length, and mobility. In addition, higher numbers of dynamic plus-ends of microtubules, resulting from microtubule-severing events, may play a role in endosomal tubulation and fission. Even so, there is growing evidence that decreased severing of microtubules does not fully explain HSP-SPG4.
The presence of two translation initiation codons in SPAST allows synthesis of two spastin isoforms: a full-length isoform called M1 and a slightly shorter isoform called M87. M87 is more abundant in both neuronal and non-neuronal tissues. Studies on rodents suggest that M1 is only readily detected in adult spinal cord, which is where nerve degeneration mainly occurs in humans with HSP-SPG4. M1, due to its hydrophobic N-terminal domain not shared by M87, may insert into endoplasmic reticulum membrane, and together with reticulons, atlastin and REEP1, may play a role in the morphogenesis of this organelle.
Some mutated spastins may act in dominant-negative fashion to lower microtubule-severing activity, but others have detrimental effects on neurons without further lowering microtubule severing. The observed adverse effects on microtubule dynamics, axonal transport, endoplasmic reticulum, and endosomal trafficking are likely caused not only by diminished severing of microtubules, but also by neurotoxicity of mutant spastin proteins, chiefly M1. Some large deletions in SPAST might also affect the function of adjacent genes, further complicating the aetiology of the disease.
SOURCE: Brain. 2015 Jun 20. pii: awv178. [Epub ahead of print] © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. PMID: 26094131 [PubMed – as supplied by publisher]
Hereditary spastic paraplegia SPG4: what is known and not known about the disease.
- 1Department of Neurobiology and Anatomy, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, PA 19129, USA.
- 2Department of Neurobiology and Anatomy, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, PA 19129, USA [email protected].