#ScienceSaturday posts share exciting scientific developments and educational resources with the KAND community. Each week, Dr. Dylan Verden of KIF1A.ORG summarizes newly published KIF1A-related research and highlights progress in rare disease research and therapeutic development.
Meet our Guest Bloggers!
This spring we’ve been quite fortunate to be joined by 6 Master’s students from Columbia University, who have been contributing to our creation of community resources as part of their Seminar in Biotechnology Course. Today Xiangyi, Haiqi, and Wenxu are here to discuss hereditary spastic paraplegia, a group of disorders causes by mutations in KIF1A (or many other genes). We’re so grateful the hard work they’ve put in this semester!
Xiangyi Liu
Xiangyi Liu is currently a student in the M.A. Biotechnology program at Columbia University. Having graduated from the B.S. program in Molecular and Cellular Biology at Wenzhou-Kean University, Liu’s previous research focused on the characterization of novel probiotics and the anti-tumor effects of pangolin scale extract on human cervical cancer. She also once interned at Wenzhou Institute, University of Chinese Academy of Sciences and participated in the research of photocurable protein-based hydrogels for developing an in vitro liver model for hepatitis drug screening.
Haiqi Chen
Haiqi Chen is a graduate student from the Department of Biological Science at Columbia University. She once worked at SACELLS Biotechnology Co. Ltd and was engaged in research related to the extraction and culture of stem cells and immune cells. During her undergraduate studies, she worked on heart disease research in Chi Kueng Lam’s laboratory at the University of Delaware. Examine the effects of modulating target proteins or genes in cardiac physiology and pathophysiology using mouse models and human induced pluripotent stem cell (iPSC) platforms.
Wenxu Ge
Wenxu Ge is a master student in Biotechnology at Columbia University (start a Ph.D. program in Chemistry in the fall of 2024). Holding a BA in Chemistry and Biochemistry from Boston University, Ge’s research is focused on the development of nanoparticles and innovative drug delivery system. In undergraduate research at Reinhard Lab, he researched HIV nanomedicine and influence of nanoplastic on GI-tract (which was published on ACS Nano). Currently, Wenxu is part of Cornish Lab at Columbia University, working on theranostic cells and synthetic biology of yeast vaccine.
KIF1A-related Research
Pluripotent Stem Cells as a Preclinical Cellular Model for Studying Hereditary Spastic Paraplegias
Pluripotent Stem Cells as a Preclinical Cellular Model for Studying Hereditary Spastic Paraplegias
Spastic paraplegia is a common feature of KAND, and also a wide variety of genetic disorders. At KIF1A.ORG we’re always on the lookout to learn from others; this week’s Review Article highlights many of the ways cell models have been used to study HSP.
Hereditary Spastic Paraplegias
Hereditary spastic paraplegia (HSP) describes a group of rare genetic degenerative disorders that affect between 1-96 people per million globally. These conditions vary, but they all involve problems with the neurons that control movement.
The core symptoms include leg spasticity, stiffness, and weakness, which in some cases results in wheelchair use. Complex HSPs can include many other symptoms like epilepsy, vision loss, and intellectual disability.
Genetics of hereditary spastic paraplegias
Mutations in various genes can cause HSPs. More than 90 spastic paraplegia genes (SPGs) and 72 loci have been identified, representing a huge variety of subtypes that impact different aspects of neuronal health:
- Protein trafficking
- Metabolism
- Neuronal growth and connections
Among the over 90 genes that cause HSPs, the differences can be attributed to the diverse functions and pathways they are involved in. In other words, each gene has specific cellular and molecular roles, such as mitochondrial function and axonal transport, which contribute to the variability in HSP phenotypes, ranging from pure form to more complex presentations. Despite this genetic diversity, the commonality of these genes arises from their unifying feature in the degeneration of the corticospinal tract. Therefore, neurons involved in movement and coordination are damaged or fail to properly develop.
KIF1A and HSP
Most of the clinical cases of AR and AD SPG30 are caused by KIF1A mutations, impairing vesicle transmission along axons. Compared with traditional HSP, mutations in KIF1A (SPG30) often lead to intellectual disability, epilepsy, cerebellar atrophy, and vision loss. One reason SPG30 causes similar symptoms to other types of HSP appears to be a shared mechanism: the degeneration of long projection axons.
Detection/ Tests
There are currently a variety of test kits used to detect the HSP gene. For example, KIF1A is included on Invitae’s HSP gene panel. Mayo Clinic laboratories has also developed next-generation sequencing (NGS) to detect HSPs. The NGS method comprises screening the whole exons to find the number of genes linked to HSP phenotypes but still poses limitations in cases of large deletions, duplications, promoter, or intronic region changes. The more we learn about genetic contributors to HSP, the more comprehensive we can make genetic screening efforts.
Limitations of animal models
The best way to understand similarities and differences between different HSP subtypes is to dig into the underlying biology. For this work we rely on model systems that reflect certain aspects of human health.
Animal models have been widely used in HSP research, but don’t always faithfully mimic all HSP symptoms. For example, zebrafish models lack corticospinal tracts which are critical for motor function and also the defective part of HSPs. Furthermore, some mouse models engineered to carry SPG mutations do not exhibit motor function impairments.
Therefore, it might be challenging for these animal models to perfectly represent the biology of motor neuronopathies in both phenotypic characterization and the identification of drugs translatable to human diseases. In addition, considering that it is expensive to screen multiple drugs in parallel with animal models, which can limit the speed of translational research.
Advantages of iPSC models
Induced pluripotent stem cells (iPSCs) are cells that are initially obtained from adult tissues and then can be reprogrammed and developed into almost any type of cell in the body.
In this case, iPSCs can be differentiated into HSP patient-specific neurons in a dish, and used to directly study the underlying biology of the patients’ affected neurons. By studying nerve cells from patients with HSPs, scientists can learn more about what goes wrong in these diseases and find new ways to help patients.
One thing iPSCs in a dish lack is a 3D structure, like you would see in an organism. This limitation of the 2D differentiation of iPSCs in vitro, however, can be mitigated by 3D iPSC culture systems. Three-dimensional iPSCs cultures, termed organoids, can stimulate complex relationship between neuronal and non-neuronal cells and the highest level of interconnection between different neuronal cell types among different brain locations (brain assembloid: combinations of multiple brain region-specific organoids). Our Research Network members at NeuCyte and the MCRI have both developed organoids to accelerate KAND research and development.
Using iPSC models to investigate HSP
Previous research in HSPs used patient-derived iPSCs to generate and study neurons carrying clinically relevant mutations. Researchers have used a variety of cellular tests to model HSPs in iPSC models. By understanding these cellular problems, scientists hope to develop new therapies that can target these specific problems and help improve the lives of patients with HSP.
In the laboratory, scientists have been studying nerve cells from SPG15 and SPG48 patients to understand how these mutations affect cell function. SPG15 is caused by mutations in the ZFYVE26 gene, while SPG48 results from mutations in the KIAA0415 gene. The ZFYVE26 gene helps cells recycle waste and produce energy. When it’s faulty, it can lead to problems in the nerves of the legs, making them stiff and weak. While SPG48 results from mutations in the KIAA0415 gene.They found that the patients’ nerve cells had problems with the mitochondria, which are like tiny power plants that power the cells. They also noted abnormalities in lysosomes, which are responsible for breaking down and recycling waste.
Another type of HSP involves mutations in a group of genes called the AP-4 complex. Patients with mutations in these genes may develop developmental delay, motor problems, and intellectual disability. The AP-4 complex is involved in helping cells transport important molecules to where they need to go. When the genes that make up this complex are mutated, it can disrupt this transport process and cause problems in cell function. Also, mutations in these genes can lead to nerve problems causing delays in development and movement issues. Understanding these cellular mechanisms could lead to the development of treatments that target the root cause of the disease, offering hope for patients affected by AP-4 complex-associated HSPs.
iPSCs in our Research Network
iPSCs are a crucial tool for our Research Network: They are currently being used to study ASOs and other gene therapies, perform drug screens, and understand KAND heterogeneity. For a deeper look at the power of iPSCs in KAND research, please check out last year’s talk by Dr. Jayne Aiken on categorizing different types of KIF1A mutations.