Spastin is a protein that plays a significant role within the human body, involved in various cellular activities. It is particularly notable in neurons, where it contributes to processes that maintain cellular structure and transport. Understanding its role in these processes provides insight into its broader impact on human health.
What is Spastin?
Spastin is a protein encoded by the SPAST gene, located on chromosome 2. It belongs to a family of proteins called ATPases Associated with a variety of cellular activities (AAA proteins). This family is involved in many cellular functions, such as regulating cell components, protein folding, and intracellular movement.
Spastin is found throughout the body, with a noticeable presence in neurons. The SPAST gene produces different forms of spastin, known as isoforms, which vary in length and transport efficiency from the nucleus to the cytoplasm.
Spastin’s Essential Function
Spastin’s primary role involves severing microtubules, rigid, hollow fibers forming the cell’s internal framework or cytoskeleton. Microtubules are dynamic structures that constantly grow, shrink, and are cut. This dynamic regulation, particularly severing, is necessary for various cellular processes.
In neurons, microtubule severing is important for axonal transport and forming new connections. Spastin forms a ring-like structure, a hexamer, which uses energy from ATP hydrolysis to pull on the C-terminal tails of tubulin, the building blocks of microtubules. This mechanical force destabilizes the microtubule lattice, causing it to break. Spastin also promotes the regrowth of severed microtubules, acting as a dual-function enzyme that both cuts and helps rebuild these structures.
Spastin and Hereditary Spastic Paraplegia
Mutations in the SPAST gene are the most frequent cause of Hereditary Spastic Paraplegia (HSP), an inherited neurological disorder. These mutations account for approximately 40% of autosomal dominant HSP cases. HSP is characterized by progressive weakness and stiffness, or spasticity, primarily in the leg muscles.
People with HSP often experience difficulties walking, stumbling, and tripping, especially on uneven surfaces. The severity and progression of symptoms vary among individuals, but many may eventually require walking aids or wheelchairs. While about 90% of individuals experience “pure” HSP, mainly affecting the lower limbs, some may have “complicated” forms with additional symptoms like nerve damage, balance issues, or vision problems.
Understanding Spastin Dysfunction in HSP
When spastin is mutated or dysfunctional, its ability to sever microtubules is impaired. This disruption in microtubule dynamics negatively impacts axonal transport. Long nerve fibers in the spinal cord, especially those in motor and sensory pathways, are vulnerable to this impaired transport.
The reduced efficiency of axonal transport leads to a “dying-back” degeneration of these long nerve fibers. This degeneration means that the farthest parts of the axons, away from the neuron’s cell body, are the first to show damage. The accumulation of disorganized microtubules, organelles, and proteins within the axons, often seen as axonal swellings, contributes to the progressive muscle weakness and spasticity observed in HSP patients.
Advancements in Spastin Research
Research focuses on improving diagnostic methods and exploring therapeutic strategies for spastin-related HSP. Studies investigate ways to increase spastin protein levels, as reduced functional spastin contributes to the disease. One promising avenue involves targeting pathways that regulate spastin’s stability, such as inhibiting its degradation.
Gene therapy approaches, including viral vectors to introduce healthy SPAST gene copies or silence mutant genes, are also being explored. Researchers are also examining drugs like HDAC6 inhibitors, which have shown potential in laboratory settings by reducing nerve damage in models of spastin-related conditions. These studies aim to develop treatments that can slow or prevent HSP progression.