Date of Award

Fall 11-22-2024

Document Type

Dissertation

Degree Name

Ph.D.

Organizational Unit

College of Natural Science and Mathematics, Biological Sciences

First Advisor

Daniel A. Linseman

Second Advisor

Daniel Paredes

Third Advisor

Sunil Kumar

Fourth Advisor

Yan Qin

Copyright Statement / License for Reuse

All Rights Reserved
All Rights Reserved.

Keywords

Amyotrophic Lateral Sclerosis (ALS), Betacyanins, Biomarkers, Fasudil, Neurodegeneration, Nutraceuticals

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a multifactorial neurodegenerative disease characterized by oxidative stress, inflammation, and motor neuron (MN) death which results in muscular atrophy. It is a relatively rare disorder, with a global frequency of 1.59 per 100,000 person years (Ilieva et al., 2023). ALS is very heterogeneous, with different symptom manifestations in the prodromal stage and varying progression rates. About 90% of all cases are sporadic with an unknown etiology, making early diagnosis challenging. The survival prognosis for patients after symptom onset is 3 to 5 years, though about 10% of patients live 10 years or longer (Feldman et al., 2022; Ilieva et al., 2023; Provenzano et al., 2023).

Dysregulation in cellular mechanisms such as autophagy, axonal transport, mitochondria homeostasis, and RNA metabolism, just to name a few, contribute to the development of disease pathology. Genetic mutations like SOD1 and C9ORF72 are observed in familial and sporadic cases of ALS. These mutations usually form aggregates of the misfolded proteins and induce oxidative stress and inflammation in the MN. Precisely, neuroinflammation and oxidation appear to be the common denominators of disease pathogenesis (De Vocht et al., 2023; Feldman et al, 2022).

In this dissertation, therapeutic and pharmaceutical treatments for ALS are explored. On chapter two, a red dragon fruit extract is used for its phytochemical properties to treat the G93A mutant hSOD1 mouse model of ALS. This betacyanin-rich red dragon fruit proves to be beneficial, as it preserves MNs in the spinal cord and protects from muscle denervation. It also extends survival significantly and ameliorates astrogliosis in the spinal cord of this ALS mouse.

On chapter three, we delved into the exploration of biomarkers and how they provide us with information about the disease state of patients. We measured different serum and CSF biomarkers to determine whether a drug had a beneficial effect in ALS patients. This pharmaceutical drug, the ROCK inhibitor Fasudil, reduces the concentration of NfL, a biomarker for neurodegeneration, in serum and CSF. It also lowers the concentrations of GFAP, an astrocytic marker, in a subset of the patients.

Continuing the work of this Fasudil clinical trial, in chapter four we explored the isolation and purification of extracellular vesicles from CSF and plasma of Fasudil-treated ALS patients. The different populations of nanovesicles isolated from these patients’ biofluids were characterized through different validation methods; thus, confirming the presence of exosomes in our extracellular vesicle fractions. We used these exosome-enriched nanovesicles to measure target engagement of Fasudil.

The work in this dissertation presents two alternative treatments for ALS. Both of them were effective and had beneficial effects on disease pathogenesis.

Copyright Date

11-2024

Publication Statement

Copyright is held by the author. User is responsible for all copyright compliance.

Rights Holder

Claudia Pena

Provenance

Received from author

File Format

application/pdf

Language

English (eng)

Extent

222 pgs

File Size

3.9 MB

Download

Available for download on Thursday, January 21, 2027



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