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Dissertation
Unraveling gain-of-toxicity and haploinsufficiency mechanisms in spastic paraplegia 4: advances through isogenic motor cortical organoids and transgenic mouse models
Doctor of Philosophy (Ph.D.), Drexel University
Jul 2025
DOI:
https://doi.org/10.17918/00011120
Abstract
Hereditary Spastic Paraplegia (HSP) is a genetically inherited neurodegenerative disorder characterized by progressive weakness and spasticity of the lower limbs, leading to distinctive gait impairment. The pathological hallmark of HSP includes swelling and degeneration of the corticospinal tracts (CST), which are axon bundles projected from upper motor neurons residing in the motor cortex. Mutations in the SPAST gene, encoding the microtubule (MT)-severing enzyme spastin, lead to Spastic Paraplegia 4 (SPG4), an autosomal dominant form of HSP that accounts for 50% of all HSP cases. Spastin has two isoforms, M1-spastin and M87-spastin, which are expressed from the same mRNA via different start codons. Emerging evidence indicates that M1-spastin and M87-spastin may carry out distinct cellular functions and are involved in different molecular pathways. To date, the SPG4 research community has been divided on etiology, often focusing on either haploinsufficiency or gain-of-toxicity from SPAST mutations without considering both mechanisms simultaneously. Previous studies have linked axon swelling as the pathological phenotype associated with haploinsufficiency, whereas axon dieback degeneration is linked to the gain-of-toxicity of mutant spastin proteins. Based on strong preliminary data we hypothesized that both pathogenic mechanisms may primarily involve M1-spastin rather than M87-spastin. We posited that impaired stress granule formation and aberrant hyperactivity of a major tubulin deacetylase, histone deacetylase 6 (HDAC6), are implicated in haploinsufficiency and gain-of-toxicity, respectively. To investigate these mechanisms, we will employed multifaceted approaches utilizing SPAST transgenic mice and isogenic hiPSC-derived motor cortical organoids enriched with upper motor neurons, the cell types most vulnerable in SPG4. Moreover, the development of these hiPSC-derived organoid models enabled the creation of patient-specific models that closely replicate human disease mechanisms, providing an advanced system for studying SPG4 in addition to traditional animal models. This approach facilitated the identification of novel therapeutic targets and accelerates the translation of research findings into clinical applications. The comprehensive nature of our studies revealed novel disease mechanisms and pave the way for identifying, validating, and developing innovative therapeutic targets for SPG4.
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Details
- Title
- Unraveling gain-of-toxicity and haploinsufficiency mechanisms in spastic paraplegia 4
- Creators
- Neha Mohan
- Contributors
- Liang Qiang (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xiii, 134 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Medicine; Pharmacology and Physiology; Drexel University
- Other Identifier
- 991022066954704721