The protein SS18L1 is a potent suppressor of polyQ-mediated huntingtin aggregation and toxicity
Modulatoren der Huntingtin-Aggregation
modulators of huntingtin aggregation
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AbstractHuntington’s Disease (HD) ist eine neurodegenerative Erkrankung, die sich durch motorische, kognitive sowie psychiatrische Beeinträchtigungen auszeichnet. Die Verlängerung eines Polyglutamin (polyQ)-Abschnittes im Protein Huntingtin (Htt) über 37 Qs hinaus bedingt die Aggregation des mutierten Proteins (mHtt) und dessen Ablagerung in neuronalen Einschlüssen. Als potenzieller Modulator der polyQ-abhängigen mHtt Aggregation und Toxizität wurde der Q-reiche Transkriptionstransaktivator SS18L1 in silico identifiziert. Rekombinantes Volllängen-SS18L1 sowie die beiden verkürzten Fragmente SS18L1_NM und SS18L1_C weisen in wässriger Lösung einen hohen Anteil an Random-Coil-Strukturen auf und bilden Oligomere. Alle SS18L1-Proteine verzögern dosisabhängig die spontane Aggregation eines Htt Exon 1 Fragmentes mit 49 Glutaminen (Ex1Q49). Dabei wird die Entstehung SDS-stabiler Ex1Q49 Aggregate durch die Stabilisierung von Ex1Q49 Mono- und Oligomeren gebremst. In HEK293 Zellen verringern rekombinante SS18L1-Proteine sowohl die Anzahl der SDS-unlöslichen Ex1Q49-Aggregate als auch die mHtt-vermittelte Zytotoxizität. Auch hierbei scheint eine Stabilisierung früher Aggregatspezies, wahrscheinlich durch die Interaktion der SS18L1-Proteine mit dem jeweiligen mHtt Fragment, eine wesentliche Rolle zu spielen. Entsprechende Interaktionen konnten mittels LUMIER-Studien und konfokaler Mikroskopie nachgewiesen werden. Humanes, exogenes SS18L1 unterdrückt die polyQ-bedingte Aggregation in einem C. elegans-Modell für HD und in transgenen R6/2 HD-Mäusen sind die Mengen an endogenem SS18L1 im Vergleich zu Wildtyp-Mäusen verändert. Beides weist darauf hin, dass SS18L1 auch in vivo von Relevanz sein könnte. Dafür spricht zudem, dass murines SS18L1 in Gehirnen von R6/2-Mäusen mit neuronalen mHtt-Aggregaten co-lokalisiert. Die Ergebnisse dieser Arbeit könnten einen Ausgangspunkt für die Entwicklung neuer Therapieansätze und die weitere Erforschung der HD Pathologie darstellen.
Huntington’s Disease (HD) is a neurodegenerative disease, which is characterised by motor, cognitive and psychiatric disturbances. The abnormal extension of an N-terminal polyQ tract in the protein huntingtin (Htt) results in aggregation of the mutant protein (mHtt) and the deposition of neuronal inclusions. The Q-rich transcriptional transactivator SS18L1 was identified in silico as a potential modulator of polyQ-mediated mHtt aggregation and toxicity. Recombinant full-length SS18L1 and the truncated fragments SS18L1_NM and SS18L1_C have a high random-coil content and form oligomeric structures in aqueous solutions. In addition, all three proteins delay the spontaneous aggregation of an Htt exon 1 fragment with a stretch of 49 glutamines (Ex1Q49). The formation of SDS-resistant Ex1Q49 aggregates is postponed in a concentration-dependent manner as monomers and oligomers, appearing early in the amyloid formation cascade, are stabilised. In mammalian cells recombinant SS18L1 proteins reduce both the number of SDS-stable Ex1Q49 aggregates and mHtt-induced cytotoxicity. These effects are likely due to the stabilisation of early aggregation intermediates, which could result from interactions of the SS18L1 proteins with the respective mutant Htt exon 1 fragment. Such interactions have been demonstrated employing a LUMIER assay and confocal microscopy. Exogenous human SS18L1 suppresses polyQ-mediated aggregation in a C. elegans model of HD and levels of endogenous SS18L1 are altered in transgenic R6/2 HD mice compared to wild type mice. As a consequence, SS18L1 might be of relevance in vivo. This is also supported by the finding that murine SS18L1 interacts with mHtt inclusions in R6/2 mice. The results of this study could provide a basis for the development of a therapeutical strategy or for the further elucidation of HD pathology.
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Formation of hippocampal mHTT aggregates leads to impaired spatial memory, hippocampal activation and adult neurogenesis.Schwab, L.C.; Richetin, K.; Barker, R.A.; Déglon, N. (2017-06)Huntington's disease (HD) is a genetic neurodegenerative disorder characterized by a triad of motor, psychiatric and cognitive deficits with the latter classically attributed to disruption of fronto-striatal circuits. However, emerging evidence suggests that some of the cognitive deficits in HD may have their origin in other structures including the hippocampus. Hippocampal abnormalities have been reported in HD mouse models particularly in terms of performance on the Morris Water Maze. However, in these animals, it is difficult to be certain whether the spatial memory deficits are due to local pathology within this structure or their poor mobility and motivation. Thus, a better model of hippocampal dysfunction in HD is needed especially given that we have previously shown that patients with HD have hippocampal-related problems from the very earliest stages of disease. In this study, our aim was therefore to understand the cellular and behavioural consequences of local overexpression of mutant huntingtin (mHTT) in the hippocampus of adult mice. We found that a targeted injection of a lentivirus, encoding an N-terminal of mHTT with 82 CAG repeats, into the murine hippocampus led to the focal formation of mHTT aggregates, long-term spatial memory impairments with decreased neurogenesis and expression of the immediate early gene c-fos. This study has therefore shown for the first time that local expression of mHTT in the dentate gyrus has deleterious effects, including its neurogenic capacity, with functional behavioural consequences, which fits well with recent data on hippocampal deficits seen in patients with HD.
What have we learned from gene expression profiles in Huntington's disease?Seredenina, Tamara; Luthi-Carter, Ruth (Elsevier, 2012)The availability of many high-quality genome-wide expression datasets has provided an exciting and unique opportunity to better understand the molecular etiology of Huntington's disease. Combining this knowledge with other aspects of huntingtin biology and disease modification screens is yielding important new insights into disease-mitigating therapeutic strategies. Having followed this line of inquiry for some time, we note that there have been a number of surprises regarding the subsequently confirmed relationships between gene expression and disease etiology. Moreover, the complexity and sheer number of proposed mechanisms by which huntingtin can perturb gene expression continues to expand. Nonetheless, ongoing efforts to enthusiastically and critically evaluate the relationships between HD pathobiology and gene expression promise to deliver accurate predictions as to which therapeutic strategies will be most effective. An exciting new arm of this research also demonstrates the power of pharmacogenomics to detect (and rule out) important neuroprotective gene expression effects. (C) 2011 Elsevier Inc. All rights reserved.
High-dose thalidomide increases the risk of peripheral neuropathy in the treatment of ankylosing spondylitisHong-xia Xue; Wen-yi Fu; Hua-dong Cui; Li-li Yang; Ning Zhang; Li-juan Zhao (Medknow Publications, 2015-01-01)Thalidomide is an effective drug for the treatment of ankylosing spondylitis but might induce peripheral neuropathy. This major adverse reaction has attracted much concern. The current study aimed to observe the incidence of thalidomide-induced peripheral neuropathy among ankylosing spondylitis patients for 1 year after treatment. In this study, 207 ankylosing spondylitis cases received thalidomide treatment, while 116 ankylosing spondylitis cases received other treatments. Results showed that the incidence of thalidomide-induced peripheral neuropathy in the thalidomide group was higher than that in the non-thalidomide group. There was no significant difference in the incidence of neuropathy between the < 6 months medication and ≥ 6 months medication groups. There were no differences in the mean age, gender, or daily dose between the two groups. The incidence of peripheral neuropathy among patients receiving 25, 50, 75, or 100 mg thalidomide per day was 4.6%, 8.5%, 17.1%, 21.7%, respectively. The incidence was significantly different between the groups receiving 25 mg and 100 mg thalidomide. In conclusion, thalidomide can induce peripheral neuropathy within 1 year after treatment of ankylosing spondylitis; however, age and gender have no obvious impact on the incidence of peripheral neuropathy. The incidence of peripheral neuropathy is associated with increasing daily doses of thalidomide.