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Mitochondrial Dysfunction in Huntington Disease
Published in Abhai Kumar, Debasis Bagchi, Antioxidants and Functional Foods for Neurodegenerative Disorders, 2021
Md. Hafiz Uddin, Marufa Rumman, Tasnuva Sarowar
At the molecular level, HD is characterized by the unusual increase in the CAG (cytosine, adenine, and guanine) triplet repeats in the first exon of HTT gene, a gene essential for mitochondrial function and early embryogenesis (Ismailoglu et al. 2014; Khatri and Man 2013). The affected individuals with HD contain extended polyglutamine repeats coded by recurrent CAG triplets. HD patients also lose GABAergic neurons in the cortex and striatum resulting from the intracellular accumulation of HTT aggregates (Zheng and Diamond 2012; Sack 2010; Costa and Scorrano 2012; Khatri and Man 2013; Lin and Beal 2006). The amplification of such trinucleotide repeats allows researchers to diagnose HD in the presymptomatic stage and even the prenatal stage because the median number of repeats in unaffected individuals is 18 while affected individuals have 36–121 repeats (median 44) (Kremer et al. 1994). Additionally, CAG length is inversely correlated with the age of disease onset (Langbehn et al. 2010). How mitochondria are involved in the normal functioning of the brain and what may go wrong in HD has been discussed below.
Degenerative Diseases of the Nervous System
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
James A. Mastrianni, Elizabeth A. Harris
The discovery that residues in ATXN1 outside of the polyglutamine tract are crucial for pathogenesis hints that alterations in the normal function of this protein are linked to its toxicity. Biochemical and genetic studies provide evidence that the polyglutamine expansion enhances interactions that are normally regulated by phosphorylation at the amino acid serine in position 776, and a subsequent alteration in its interaction with other cellular proteins.24
Relation of Antigliadin Antibodies to Gluten-Sensitive Enteropathy
Published in Tadeusz P. Chorzelski, Ernst H. Beutner, Vijay Kumar, Tadeusz K. Zalewski, Serologic Diagnosis of Celiac Disease, 2020
Wim Th. J. M. Hekkens, Marja van Twist - de Graaf
These structures, be they primary, secondary, tertiary, or even quaternary, are unique for the different gliadin proteins. This means that the gliadin proteins are heterogeneous for parts of the molecule and, consequently, differ in physical and chemical properties. One of these properties is the polarity of the different parts of the molecule. In general, gliadin contains many neutral amino acids and, thus, has large hydrophobic regions in the molecule. The regions of polyglutamine that can be found in the molecule and the proline-containing regions are especially hydrophobic. Interaction with other hydrophobic molecules can be explained in this way. Aggregation also depends on the low charge of the gliadin molecules. The tertiary and quaternary shape of the molecule is based on the same principles, apart from the high proline content that prevents the formation of α-helix structures over larger parts of the molecule. About 13% of the gliadin molecule is in the α-helix form, whereas 58% of the molecule consists of β-turns. The remaining part has a random structure. These forms have consequences for the immunogenicity of the different molecules. β-Turns are especially immunogenetic and are found in the more nonpolar parts of the gliadin molecules.
Current and emerging treatment modalities for spinocerebellar ataxias
Published in Expert Review of Neurotherapeutics, 2022
Shaila D. Ghanekar, Sheng-Han Kuo, Joseph S. Staffetti, Theresa A Zesiewicz
The most common SCAs are caused by polyglutamine (poly Q)-encoding CAG repeat expansions in respective genes, which cause dysfunctional conformation of protein structure and subsequent aggregation and intranuclear inclusions [10]. The length of the repeats in these polyglutamine SCAs correlates with aggregation tendency and inversely with age of onset; increasing repeat length is linked with earlier age of onset and increased aggregation tendency [1,6]. The exact role of inclusions is unclear, but the dysfunctional confirmation of the polyglutamine disease protein causes neuronal stress and disruption of cellular homeostasis [6,10]. SCAs with polyglutamine repeat expansions (SCA 1, 2, 3, 6, 7, and 17) tend to exhibit ‘anticipation,’ such that ensuing generations suffer earlier onset and more severe symptoms [1]. While SCA12 is also caused by pathological expanded CAG repeats, these CAG repeats are located in the untranslated region; therefore, SCA12 is not considered a polyglutamine SCA [11]. The non-polyglutamine SCA diseases may also cause altered protein function via point mutations and repeat expansions in noncoding regions, as proteotoxicity appears to play a role in disease pathogenesis [6]. Mitochondrial dysfunction and voltage-dependent ion channel dysfunction of cerebellar neurons also contribute to SCA pathophysiology [12,13].
Investigating TBP CAG/CAA trinucleotide repeat expansions in a Taiwanese cohort with ALS
Published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2021
Kang-Yang Jih, Kon-Ping Lin, Pei-Chien Tsai, Bing-Wen Soong, Yi-Chu Liao, Yi-Chung Lee
SCA17 is a dominantly inherited neurodegenerative disease, characterized by ataxia (95%), dementia (∼90%), and involuntary movements (∼70%) such as chorea and dystonia (5–7). Psychiatric symptoms, pyramidal signs, and rigidity are also common manifestations (8,9). SCA17 is caused by an abnormal expansion of the CAG/CAA trinucleotide repeats within TBP. It is categorized as a polyglutamine disease since both CAG and CAA encode glutamine and the expanded trinucleotide repeats will result in a mutant TBP protein with a prolonged polyglutamine expansion. The normal trinucleotide repeat length in TBP ranges from 25 to 40. Patients carrying the TBP mutant allele with a CAG/CAA repeat size greater than 49 would develop SCA17 with complete penetrance, whereas those with intermediate-length CAG/CAA repeats (41 to 48) are at risk of SCA17 with a reduced penetrance (10). Only few SCA17 patients with 41 − 43 CAG/CAA repeats have been reported (11–13), and the majority of SCA17 cases carry TBP alleles with 44 or more CAG/CAA repeats (6,7).
Discovery of drugs that directly target the intrinsically disordered region of the androgen receptor
Published in Expert Opinion on Drug Discovery, 2020
AR-NTD is largely unstructured and described as having limited stable secondary structure which can be induced by interactions with binding partners to increase α-helical content and thereby conforms to a molten-globule-like conformation referred to as ‘collapsed disordered’ [13–15] (Figure 2(a)). This domain is the most abundantly post-translationally modified of the AR and acts as a hub for interactions with many other proteins (Figure 2(b)). Most importantly is interaction of this domain with the basal transcriptional machinery that is necessary for its transcriptional activity. Within AR-NTD is AF-1 which is estimated to have 13% helical secondary structure but this can increase upon interaction with a binding partner [13,14]. AF-1 is comprised of two transactivation units 1 and 5 (Tau-1 and Tau-5). Tau-1 is comprised of amino acid residues 101–370 of which a large number are acidic amino acids. Tau-5 is comprised of amino acid residues 360–485 and is not acidic. Interestingly AR-NTD harbors several repeat regions for glutamine (polyglutamine tract or polyQ), proline, alanine, and glycine.