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Caenorhabditis elegans Aging is Associated with a Decline in Proteostasis
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
Polyglutamine (polyQ) disorders are a family of nine different neurodegenerative disorders all of which are caused by an expansion of a polyQ tract, albeit in different proteins, each encoded by a cytosine-adenine-guanine (CAG) trinucleotide repeat in the corresponding gene. As such, these are heritable genetic disorders and include HD, Machado–Joseph disease (MJD), spinobulbar muscular atrophy (SBMA), dentatorubral–pallidoluysian atrophy (DRPLA), and five SCAs. For all of these diseases, the polyQ expansion destabilizes the affected protein thereby disrupting the thermodynamics of folding and causing protein misfolding and aggregation. Outside of the polyQ tract itself, each of the affected proteins in each of these diseases share no common sequences or functions. The key to disease is thus the polyQ tract, such that the age of disease onset and symptom severity is inversely proportional to the length of the polyQ tract [21–23].
Hereditary Spastic Paraparesis and Other Hereditary Myelopathies
Published in Anand D. Pandyan, Hermie J. Hermens, Bernard A. Conway, Neurological Rehabilitation, 2018
Jon Marsden, Lisa Bunn, Amanda Denton, Krishnan Padmakumari Sivaraman Nair
Depending on ethnicity, SCA3 accounts for between 21 and 56% of SCA cases.107 Prevalence varies according to founder effects. It is a polyglutamate (polyQ) disease caused by a CAG repeated expansion of the ATXN3 gene on chromosome 14q. The protein encoded by ATXN3, ataxin-3, is a deubiquitinating enzyme that cleaves ubiquitin off substrates. It is felt that this enzyme’s function, and thus biochemical pathways dependent upon ubiquitin, are affected in SCA3.108 The age of onset varies from childhood to late adult life and there is an inverse correlation between the number of CAG repeats and the age of onset and disease severity.109
Neuroprotective effects of rutin on ASH neurons in Caenorhabditis elegans model of Huntington’s disease
Published in Nutritional Neuroscience, 2022
Larissa Marafiga Cordeiro, Marcell Valandro Soares, Aline Franzen da Silva, Marina Lopes Machado, Fabiane Bicca Obetine Baptista, Tássia Limana da Silveira, Leticia Priscilla Arantes, Felix Alexandre Antunes Soares
The idea that some polyphenolic compounds may interfere with protein aggregation is not new. Flavonoids are considered to be the major category of dietary polyphenols; for example, rutin is a citrus flavonoid glycoside, which is a low-molecular-weight polyphenolic compound. Wanker et al. [31] found that epigallocatechingallate (EGCG), a green tea polyphenol, modulates misfolding and oligomerization of the expanded polyQ proteins, resulting in efficient suppression of polyQ aggregation in vitro [31]. EGCG suppressed aggregation formation of the polyQ proteins, and polyQ-induced cytotoxicity, in HD models of yeast and Drosophila [31], and in the SCA3 model of C. elegans [32]. Curcumin inhibited tau [33], α-synuclein [34], and Htt protein [35], and acted as an activator of molecular chaperones in polyQ diseases [33, 35]. Finally, our own studies have shown that chronic rutin treatment reduced polyQ protein aggregation in muscle, and reduced polyQ-mediated neuronal death in ASH neurons [7]. No specific drugs are available to counter the pathology of polyQ aggregates, and current treatments have multiple side effects; there is an urgent need, therefore, to find natural modulators with neuroprotective effects against polyQ diseases.
Advances in the understanding of hereditary ataxia – implications for future patients
Published in Expert Opinion on Orphan Drugs, 2018
Anna Zeitlberger, Heather Ging, Suran Nethisinghe, Paola Giunti
A plethora of causative mutations have been described in dominant inherited ataxias, including: conventional mutations (SCA5, SCA11, SCA13, SCA14, SCA19/22, SCA23, SCA26, SCA27, SCA28, SCA19, SCA35); rearrangements (SCA15, SCA16, SCA20); as well as expansions of variable length in intronic (SCA8, SCA10, SCA12, SCA31, SCA36) and exonic regions (SCA1, SCA2, SCA3, SAC6, SCA7, SCA17, DRPLA) [23]. The latter encompass the most common and best-studied dominantly inherited ataxias. Together with other late-onset neurodegenerative diseases, namely HD and spinal-bulbar muscular atrophy, they form the group of nine known polyglutamine (polyQ) diseases. These disorders share an exonic (CAG)n TR expansion in their respective disease genes [24–26]. Simple repetitive elements are considered pathological if the number of triplets is greater than the number found in wild-type alleles [27]. Once above a critical threshold, the excessive polyQ stretches in the translated proteins promote cell-specific degeneration associated with a toxic gain-of-function at the protein and mRNA level, which leads to the pathological hallmark of these disorders, cellular aggregation [28].
The efficacy and safety of riluzole for neurodegenerative movement disorders: a systematic review with meta-analysis
Published in Drug Delivery, 2018
Neurodegenerative movement disorders include Parkinson’s disease (PD), atypical parkinsonisms, Huntington disease (HD), and hereditary ataxia, which are characterized by neuron loss and gliosis with clinical motor symptoms (Liu & Wang, 2014). Non-motor symptoms are probably seen in the course of diseases, such as hyposmia, dementia, and autonomic dysfunction. Sporadic PD and atypical parkinsonisms are usually age-related and attributed to tauopathy [progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD)] or synucleinopathy [PD and multiple system atrophy (MSA)] (Dickson, 2012). While HD and hereditary ataxia are hereditary polyglutamine (PolyQ) diseases with early-onset (Katsuno et al., 2014). At present, neurodegeneration and diseases progression cannot be completely prevented by any interventions. The current clinical therapy is mainly focused on relieving symptoms (e.g. hypokinesia, hyperkinesia, or ataxia) and neuroprotective effects (Tsou et al., 2009; Liu et al., 2014; Liu & Wang, 2017).