Genetic Mechanisms of Hereditary Spastic Paraplegia

Hereditary spastic paraplegia (HSP) comprises a group of inherited neurodegenerative disorders characterised by progressive spasticity and weakness of the lower limbs. At its core, HSP arises from mutations that disrupt axonal maintenance in corticospinal motor neurons, often through perturbations of intracellular membrane dynamics, organelle morphology and cytoskeletal regulation. More than 80 genetic loci have been implicated, encompassing autosomal dominant, autosomal recessive and X-linked inheritance patterns. The encoded proteins participate in diverse cellular processes: shaping the endoplasmic reticulum network, severing microtubules, regulating membrane trafficking and overseeing lipid homeostasis. Mutations in ER-shaping proteins can alter membrane curvature and tubule stability, while defects in microtubule-severing enzymes lead to impaired axonal transport. Ubiquitin-mediated turnover of key proteins and gene dosage effects such as haploinsufficiency further contribute to pathogenesis. Recent advances in structural biology, model organisms and patient-derived cells have illuminated how subtle disruptions in protein self-association, ubiquitination pathways and lipid metabolism converge on a common pathway of axonal degeneration. These insights underpin emerging precision therapies that aim to restore protein levels, correct lipid imbalances or deliver functional genes to affected neurons.

Research from Nature Portfolio

A study on reticulon-like proteins has revealed how oligomeric scaffolding stabilises tubular domains of the endoplasmic reticulum. Using structure prediction and cross-linking, researchers showed that hairpin-forming segments within the REEP family drive homotypic dimerization and higher-order assembly, generating membrane curvature without relying solely on an intrinsic wedge. Strikingly, HSP-causing mutations in REEP1 were found at oligomeric interfaces, weakening self-association and compromising ER network integrity. These findings suggest that failure of ER curvature generation by mutant scaffolds is a primary pathogenic mechanism in certain dominant forms of HSP.

Genetic Mechanisms of Hereditary Spastic Paraplegia publication trend

The graph below shows the total number of articles in genetic mechanisms of hereditary spastic paraplegia across all publications each year (not limited to Nature Index journals).

Technical terms

Endoplasmic reticulum: A membrane network involved in protein and lipid synthesis, folding and trafficking.

Oligomerization: The assembly of protein subunits into a multi-unit complex necessary for function or structural stability.

Haploinsufficiency: A condition in which a single functional copy of a gene does not produce enough protein for normal function.

E3 ubiquitin ligase: An enzyme that facilitates attachment of ubiquitin to target proteins, marking them for degradation or regulation.

Gene therapy: The introduction of functional genetic material into cells to compensate for defective genes.

References

1. Oligomeric scaffolding for curvature generation by ER tubule-forming proteins. Nature Communications (2023).
2. Cul-4 inhibition rescues spastin levels and reduces defects in hereditary spastic paraplegia models. Brain (2024).
3. AMFR dysfunction causes autosomal recessive spastic paraplegia in human that is amenable to statin treatment in a preclinical model. Acta Neuropathologica (2023).
4. Paving a way to treat spastic paraplegia 50. Journal of Clinical Investigation (2023).