Hereditary spastic paraplegia type 4

This blog will discuss Hereditary spastic paraplegia type 4, from the aspect of pathophysiology, diagnosis, and treatment. I will mainly focus on pathophysiology.

    

Content:
1. What is Hereditary spastic paraplegia (HSP)
2. Types of HSP

3. Epidemiology

4. Corticospinal tract

5. SPG4

6. Spastin domain & isoform

7. Spastin function

8. Mutation

9. Diagnosis

10. Treatment & Prevention

11. References

1. What is Hereditary spastic paraplegia (HSP)?

Hereditary spastic paraplegia (HSP) is also known as familial spastic paraparesis (FSP), or Strümpell-Lorrain syndrome. 

The definition of the HSP can be learned through its name 

• "HEREDITARY": inherited;
• "SPASTIC": means the increase of muscle tone;
• "PARAPLEGIA": a type of paralysis that affects the lower half of body. 

So HSP refers to a group of rare, inherited, and degenerative neurological disorders with a defining feature of prominent lower extremity spasticity due to the degeneration of upper motor neuron or corticospinal tract. 

2. Types of HSP?

HSP syndromes can be classified into two types in general. 

• “Pure” HSP: Symptoms are confined to leg weakness and tightness, and urinary urgency only. 
• “Complex” HSP: Symptoms are leg weakness and spasticity while accompanied by other additional neurologic disturbance. 

Inheritance patterns include:

• Autosomal dominant: such as SPG4, SPG3A, SPG10, SPG31, and so on.
• Autosomal recessive: such as SPG11, SPG5, SPG11, SPG15, and so on.
• X-linked: SPG1 (complex but rare)
• Mitochondrial inheritance: Only inherited from mother  (rare)

3. Epidemiology

• The prevalence of HSP is highly variable, ranging from 1/11,000-77,000 in Europe. 
• The onset of symptoms varies from infancy to older than 60 years. 
• There is no accurate or specific data to tell exactly how many people is having HSP so far because it is often misdiagnosed. 
• Moreover, this HSP disease will affect males and females of all ethnic groups from around the world. 
• The life expectancy of HSP patients is normal, but their symptoms will gradually get worse over time. As the condition progresses, some patients might require wheelchair assistance.

4. Corticospinal tract

The corticospinal tract is the main CNS pathway controlling voluntary movement, which encompasses connections between the cerebral motor cortex and the spinal cord.

Axons of the upper motor neurons, which originate in the cerebral motor cortex, pass through the medullary pyramids, where most axons decussate to form the lateral corticospinal tract in the spinal cord. 

These axons establish synapses directly or indirectly with the lower motor neurons in the spinal cord anterior horn(spinal grey matter). The indirect connections are via interneurons. The axons of the lower motor neurons synapse at neuromuscular junctions to mediate skeletal muscle contraction.

Hence, when length-dependent, distal degeneration of corticospinal tract axons occur, HSP is present.

(Degeneration includes corticospinal tracts, fasciculus gracilis, and spinocerebellar tracts. These fibers tracts contain the longest axons of the nervous system.)

In HSP patients, their upper motor neurons slowly degenerate, causing the lower motor neuron did not receive adequate nerve impulses. In effect, the muscles cannot move if there is no signal received, and when the muscles do not move for a long time, they become weak and stiff. 

Corticospinal tract

5. SPG4 

Gene symbol locus: SPAST 2P24-p21

SPG4 is the most common gene of autosomal dominant HSP. 

It accounts for 40% in autosomal dominant HSP. 

In this inheritance pattern, each child has a 50% chance to inherit the mutation from an affected parent.

Key clinical features:

• Highly variable onset. 
• Late-onset cognitive impairment.
• Rarely complicated with dementia, cerebellar ataxia, thin corpus callosum
• Usually is "pure" form of HSP

Frequency: The prevalence is estimated to be 2 to 6 in 100,000 people worldwide.

Percentage of Autosomal dominant HSP

6. Spastin domain & isoform

SPG4 encoded a microtubule-severing protein called spastin. It has four domains.

The hydrophobic region (HR) and microtubule interacting and trafficking domain (MIT) are important for membrane modeling processes. While microtubule-binding domain (MBD) and AAA ATPase domain are essential in microtubule serving.

• HR: forms an intramembrane hairpin loop. 
• MIT: forms a three-helix bundle that interacts with a helix in the endosomal sorting complex required for transport III (ESCRT-III) proteins. This refers to charged multivesicular body protein 1B (CHMP1B) and IST1. 
• MBD: The domain for spastin to bind to microtubules.
• AAA ATPase: contains the enzymatic activity of the protein that is vital for microtubule breakage.

Spastin domain

SPG4 gene has two start codons(AUG) that produce two spastin isoforms, which is M1 and M87. 

As you can observe in the picture, the difference between M1 and M2 is the presence of the N-terminal domain. With the hydrophobic N-terminal domain, M1 spastin is a 616 amino-acid a full-length isoform. While M87 spastin is a slightly shorter isoform that lacks the first 86 amino acids. 

M1 is only present in the adult spinal cord while M87 is present in various tissue.

Spastin isoforms: M1 & M87

7. Spastin function

Spastin is a microtubule-severing protein, a member of the AAA protein family. This protein family plays a role in many cellular activities, including the regulation of cell components and proteins.  

Spastin can be found throughout the body, especially in neurons. 

Spastin regulates microtubule organization via destabilize tubulin-tubulin connections. This involved the carboxy-terminal half of spastin, which are the microtubule-binding domain (MBD) and AAA ATPase domain. 

As fundamental, microtubules are a tubular structure made of α- and β-tubulin heterodimers. 

• α-tubulin subunit is exposed at the minus end
• β-tubulin subunit is at the plus end of the microtubule. 

Both of these tubulin dimers can bind two molecules of GTP. One of the GTP molecules can be hydrolyzed subsequent to assembly. This hydrolysis process needs ATP to regulate. 

GTP bound to α-tubulin is stable and it maintains the structural. While GTP bound to β-tubulin may be hydrolyzed to GDP shortly after assembly. Different from those of GTP-tubulin,  GDP-tubulin is more prone to depolymerization. 

In simple terms, depolymerization is the process of breaking down large molecules into smaller molecules. If a GDP-bound tubulin subunit at the tip of a microtubule will tend to disassembly, which means the microtubule will not maintain a tubular structure. Hence, as you can observe in the figure.

Microtubules are capped at their ends by stabilizing regions enriched in GTP tubulin, also known as GTP cap. This GTP cap is responsible to protects the central which is GDP-containing region from depolymerization. 

Microtubules serving

Polyglutamylation is a process that adding multiple glutamates to the C-terminal tails of tubulin which is exposed to the outer surface of the tubules. This process increases the negative charge of C terminal tails. Therefore, it promotes MBD which is positive charge, binds with microtubules, and conducts the serving activity. 

Polyglutamylation

The severing activity causes the GDP region exposes and the newly created plus end to shrink. This is because these newly cut-down fragments lose its cap and thus undergo depolymerization, which leads to the disassembly of microtubules. Or we can say decrease the length of microtubules. This switch from growth to shrinking is called a catastrophe.

Normally, microtubules will maintain a dynamic instability which is defined as microtubules constantly switch between growing and shrinking states. 

So, when the length of the microtubule dramatically decreases, it will conduct the polymerization and regrow. This is also known as a rescue event. 

This dynamic instability is essential as it allows microtubules to change rapidly to respond cellular needs. For example, reorganization of the cytoskeleton in the transition to mitosis and the extension of growth cones from neurons.

8. Mutation

However, when the mutation occurs to decrease the production of spastin or mutation in MBD and AAA ATPase domain, affect the binding of proteins to microtubule and inhibit the ATP hydrolysis, leads to hyperstabilization of microtubules. Further, impair the microtubules’ ability to transport organelles, which linking to cell movement that ultimately causes contraction in muscle cells.

As a result, it causes corticospinal tract defects, leads to spasticity. 

(SPG4 mutation including missense, nonsense and splice-site.)

 

9. Diagnosis

HSP can be diagnosed by 

• Typical symptoms: such as lower extremity spastic weakness.....
• Family history: should be aware as HSP is an inherited disease
• MRI scan:
• demonstrates specific abnormalities including reduced size of the corpus callosum
• help exclude other disorders such as multiple sclerosis 
• Genetic testing: 
• Maybe has de novo mutation, which means the mutation first time occurs in a person with no family history. It is estimated 30% of individuals with HSP do not have documented family history. 

10. Treatment & Prevention

There are currently no treatments to prevent, stop, or reverse the degenerative process. 

Therefore, treatment is focused on symptom relief such as 

• Medication for spasticity 
• Tizanidine
• short-acting drug useful for treating nocturnal spasms and for intermittent management of spasticity by blocking nerve impulses to brain
• Diazepam
• sedatives that slow the central nervous system
• Clonazepam 
• sedatives that slow the central nervous system
• Dantrolene
• reduce muscle contraction but may cause liver damage
• Physical therapy 
• Stretching
• Aerobic Exercise 
• Strengthening 

11. References:

Blackstone, C., O'Kane, C. J., & Reid, E. (2011, January). Hereditary spastic paraplegias: membrane traffic and the motor pathway. Nature reviews. Neuroscience. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5584382/.

Daumke, O., & Praefcke, G. J. (2011). Structural insights into membrane fusion at the endoplasmic reticulum. Proceedings of the National Academy of Sciences, 108(6), 2175–2176. https://doi.org/10.1073/pnas.1019194108

Lacroix, B., van Dijk, J., Gold, N. D., Guizetti, J., Aldrian-Herrada, G., Rogowski, K., Gerlich, D. W., & Janke, C. (2010, June 14). Tubulin polyglutamylation stimulates spastin-mediated microtubule severing. The Journal of cell biology. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2886356/.

Spastic Paraplegia Foundation. (n.d.). Treatment and Therapies. Retrieved from https://sp-foundation.org/understanding-pls-hsp/treatments.html​

U.S. National Library of Medicine. (2021, April 27). Spastic paraplegia type 3A: MedlinePlus Genetics. MedlinePlus. https://medlineplus.gov/genetics/condition/spastic-paraplegia-type-3a/.

U.S. National Library of Medicine. (2021, April 27). Spastic paraplegia type 4: MedlinePlus Genetics. MedlinePlus. https://medlineplus.gov/genetics/condition/spastic-paraplegia-type-4/.

National Center for Advancing Translational Sciences. (2021, February). Hereditary spastic paraplegia. Retrieved from https://rarediseases.info.nih.gov/diseases/6637/hereditary-spastic-paraplegia

Yin-Wei Kuo, & Jonathon Howard. (2020, November 9). Cutting, Amplifying, and Aligning Microtubules with Severing Enzymes. Trends in cell biology. https://www.cell.com/trends/cell-biology/fulltext/S0962-8924(20)30210-5. 

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