Innovative KIF5A Roles in Neurodegenerative Diseases

KIF5A Structure and Its Impact on Neuronal Function

KIF5A is a member of the kinesin family of molecular motors, characterized by its ability to transport cargo along microtubules in a process that is energy-dependent and ATP-driven. Structurally, KIF5A consists of a motor domain, a coiled-coil stalk, and a tail domain. The motor domain is responsible for microtubule binding and ATP hydrolysis, while the tail region interacts with specific cargoes through adaptors, such as kinesin light chains (KLCs) (Cozzi et al., 2024).

The unique structure of KIF5A allows it to engage in various transport processes, including the delivery of neurofilaments, synaptic vesicles, and organelles like mitochondria. Disruption in these transport mechanisms, due to mutations in KIF5A, can lead to the accumulation of neurotoxic substrates and contribute to neuronal degeneration (Cozzi et al., 2024).

Table 1: Key Structural Features of KIF5A

KIF5A Mutations Linked to Spastic Paraplegia and CMT

Mutations in KIF5A are implicated in several hereditary spastic paraplegias, notably SPG10. These mutations often cluster in the motor and stalk domains of the protein, leading to impaired transport capabilities. For instance, point mutations such as p.R280C have been shown to disrupt KIF5A’s ability to bind to microtubules effectively, resulting in the accumulation of cargoes in the neuronal cell body (Cozzi et al., 2024).

In the case of CMT, which is characterized by axonal degeneration, KIF5A mutations lead to similar transport deficits. The pathogenic mechanisms underlying these diseases suggest that KIF5A mutations can result in a loss of function (LOF) or a gain of function (GOF), depending on the nature of the mutation. While LOF mutations typically lead to reduced transport efficiency, GOF mutations can cause aberrant aggregation of the protein, exacerbating cellular dysfunction (Cozzi et al., 2024).

Mechanisms of KIF5A in Axonal Transport and Mitochondria

KIF5A is critical for the transport of various cargoes along the axons, including neurofilaments and synaptic vesicles. The transport mechanisms involve a complex interplay between KIF5A and its adaptors, which link the motor protein to specific cargoes. The efficient transport of mitochondria is particularly vital, as these organelles are essential for energy production and calcium homeostasis in neurons. Disruption in mitochondrial transport due to KIF5A mutations can lead to neuronal degeneration and is linked to diseases such as ALS (Cozzi et al., 2024).

Table 2: Cargoes Transported by KIF5A

KIF5A’s Influence on Amyotrophic Lateral Sclerosis Pathology

The association between KIF5A mutations and ALS has garnered significant attention in recent years. Frameshift mutations in KIF5A result in the production of elongated proteins that lose their autoinhibitory properties, leading to enhanced motility and aggregation within the neuronal cytoplasm (Cozzi et al., 2024). These aggregates are thought to disrupt normal axonal transport, leading to cell death. The presence of KIF5A aggregates has been observed in ALS patients, supporting the hypothesis that transport deficits contribute to the disease’s pathology.

Additionally, studies have indicated that KIF5A mutations may alter the transport dynamics of critical proteins involved in synaptic transmission, further exacerbating the neurodegenerative process (Cozzi et al., 2024).

Neonatal Intractable Myoclonus: KIF5A’s Genetic Connection

NEIMY is characterized by severe myoclonic seizures during the neonatal period, caused by specific KIF5A mutations that lead to functional deficits in neuronal transport mechanisms. These mutations typically result in elongated protein products that aggregate and disrupt normal cellular function, contributing to the severe clinical manifestations observed in affected individuals (Cozzi et al., 2024).

Table 3: Clinical Phenotypes Associated with KIF5A Mutations

Conclusion

KIF5A plays a crucial role in neuronal function, and its mutations are linked to a range of neurodegenerative disorders. Understanding the structure and function of KIF5A not only sheds light on the pathophysiology of diseases like SPG10, CMT, ALS, and NEIMY but also opens avenues for the development of targeted therapies. Future research should focus on elucidating the precise molecular mechanisms by which KIF5A mutations lead to neuronal dysfunction, as well as exploring potential therapeutic interventions aimed at restoring normal transport processes.

FAQ

What is KIF5A?
KIF5A is a kinesin family member that functions as a molecular motor, essential for transporting cellular cargo along microtubules in neurons.

What diseases are associated with KIF5A mutations?
KIF5A mutations are associated with spastic paraplegia type 10 (SPG10), Charcot-Marie-Tooth disease (CMT), amyotrophic lateral sclerosis (ALS), and neonatal intractable myoclonus (NEIMY).

How do KIF5A mutations affect neuronal function?
KIF5A mutations can lead to defective transport mechanisms, resulting in cargo accumulation, disruption of mitochondrial transport, and ultimately neuronal degeneration.

What therapeutic strategies are being explored for diseases linked to KIF5A?
Research is ongoing to identify targeted therapies that could restore normal transport functions in neurons affected by KIF5A mutations.

References

1. Cozzi, M., Tedesco, B., Ferrari, V., Chierichetti, M., Pramaggiore, P., Cornaggia, L., … & Poletti, A. (2024). One gene, many phenotypes: the role of KIF5A in neurodegenerative and neurodevelopmental diseases. Cell Communication and Signaling, 22(1), 27. DOI: 10.1186/s12964-025-02277-x

2. Fink, J. K. (2013). Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms. Acta Neuropathologica, 126(3), 307-328.

3. Nicolas, A., Kenna, K. P., Renton, A. E., Ticozzi, N., Faghri, F., Chia, R., … & Riva, N. (2018). Genome-wide analyses identify KIF5A as a novel ALS gene. Neuron, 97(6), 1268-1286. DOI: 10.1016/j.neuron.2018.02.027

4. Brenner, D., Yilmaz, R., Müller, K., Grehl, T., Petri, S., & Meyer, T. (2018). Hot-spot KIF5A mutations cause Familial ALS. Brain, 141(3), 688-697. DOI: 10.1093/brain/awx370

5. Duis, J., et al. (2016). Neonatal intractable myoclonus associated with KIF5A mutations. Nature Genetics, 48, 1663–1670.