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Authors
Advisor(s)
Abstract(s)
Since the early 90’s a new class of inherited neurodegenerative diseases has been
characterized, the polyglutamine (polyQ) expansion diseases. This group is composed by
nine progressive and finally fatal disorders. The mutation underlying each one of these
disorders is an expansion of a CAG trinucleotide repeat that encodes a polyQ tract in the
respective disease proteins. This polyQ expansion causes the appearance of misfolded
protein species, which ultimately lead to the formation of aggregates and neuronal loss.
Although polyQ diseases present different clinical features and neuronal degeneration
pattern, all these diseases have in common the fact that the associated gene products are
widely expressed but affect only specific subsets of neurons. This specificity suggests that
protein misfolding and its toxic outcomes may be determined by the polyQ-flanking
sequences of the specific disease-associated proteins. Machado-Joseph disease (MJD) or
spinocerebellar ataxia type 3 (SCA3) is the most frequent autosomal dominant ataxia
worldwide. Ataxin-3 (ATXN3) is a polyQ protein and expansion of its repetitive glutamine
tract causes MJD. The economic and social impact of these neurodegenerative diseases has
led several researchers worldwide to investigate the pathogenesis mechanism and
therapeutic strategies for polyQ diseases. Animal models, like Caenorhabditis elegans (C.
elegans), have proved to be an essential tool in this field due to their importance in the
development of therapeutic trials.
C. elegans offers unique advantages for examining the aggregation dynamics of
aggregation-prone proteins and its toxic effects on individual neurons, since the
transparency of all 959 cells allows easy detection of fluorescent proteins in live animals.
Despite having relatively few neurons, C. elegans display a wide array of complex
behaviors and a clear link exists between the behavior and the function of neuronal subsets.
In this work, we used a C. elegans model of MJD for a screening of therapeutic
compounds. First, we have tested the effect of a candidate compound targeting
mitochondrial toxicity: creatine (Cr). We showed that, in our C. elegans model of MJD
pathogenesis, Cr food supplementation had limited effect in mutant ATXN3-mediated
neuronal dysfunction and aggregation. Further experiments will be required to determine
Screening of therapeutic compounds in a C. elegans model of Machado-Joseph disease:
targeting mitochondria.
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the treatment effectiveness. Next, in a hypothesis-free approach, we have tested 20
compounds from an FDA-approved out-of-patent library, and the small molecules Prestw
38 and Prestw-227 significantly reduced mutant ATXN3-mediated motor impairment.
In summary, with this work we have identified two compounds that reduced the
percentage of mutant ATXN3 animals that present locomotion defects, and one of which
showed a significant reduction in the number of aggregates per area and in the area of
aggregates per area. It also made available a valuable C. elegans model/tool for drug
discovery and target identification that can be very useful in future therapy development in
MJD.
Description
Keywords
Machado-Joseph disease ataxin-3 protein aggregation neuronal dysfunction mitochondrial dysfunction creatine small molecules