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Applications of imaging genomics beyond oncology
Published in Ruijiang Li, Lei Xing, Sandy Napel, Daniel L. Rubin, Radiomics and Radiogenomics, 2019
Xiaohui Yao, Jingwen Yan, Li Shen
One GWAS has identified a novel gene transmembrane protein 106B (TMEM106B) associated with FTD-TDP, as well as increased risk of FTLD-TDP in individuals with GRN mutations [89]. Several other rare FTD risk genes, including charged multivesicular body protein 2B (CHMP2B), valosin containing protein (VCP), sequestosome 1 (SQSTM1), transactive response DNA-binding protein (TARDP), FUS, Tank-binding kinase 1 gene (TBK1), and coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10), have also been reported in small family studies [81, 86–88, 90–92]. Diekstra et al. [93] performed a meta-analysis of GWAS and reported two shared genetic associations of FTD and ALS including C9orf72 and a novel gene unc-13 homolog A (UNC13A). Although the above common and rare genetic findings have contributed to the risk of different types of FTLD, some portion of disease heritability is still unexplained. In addition, the molecular mechanism of disease is not fully understood due to limited statistical power of case-control study and complex pathology of FTD.
Progress, development, and challenges in amyotrophic lateral sclerosis clinical trials
Published in Expert Review of Neurotherapeutics, 2022
Jasmine F. Ashhurst, Sicong Tu, Hannah C. Timmins, Matthew C. Kiernan
In terms of genetic susceptibility, UNC13 proteins have been identified as presynaptic proteins that are essential for synaptic vesicle exocytosis and regulation of the release of neurotransmitters [97]. Of relevance, UNC13A has been identified as a susceptibility gene for ALS and FTD [98–100]. A meta-analysis assessed outcomes of treatment with lithium carbonate within genetic subgroups of ALS patients, including patients with UNC13A and C9orf72 genotypes and non-carriers [101]. Large-scale clinical trials determined that while lithium carbonate treatment showed no significant benefit in carriers of C9orf72 or non-carriers, there was a significant effect measured in UNC13A carriers, with a 70% reduction in the number of patients who died in the 12 month follow-up period compared to the placebo group. This study highlighted the importance of incorporating genetic information in ALS clinical trials, as some treatment benefits may be genotype specific. As such, clinical trial therapies that are determined to improve outcomes in specific ALS genotypes will be further assessed in those genotypes, facilitating precision therapy.
What do we know about the variability in survival of patients with amyotrophic lateral sclerosis?
Published in Expert Review of Neurotherapeutics, 2020
Pamela A. McCombe, Fleur C Garton, Matthew Katz, Naomi R Wray, Robert D Henderson
Other studies have identified variants contributing to ALS risk in GWAS and subsequently tested their association with survival, this includes rs12608932 (UNC13A). This association has been identified in certain European cohort studies (Dutch, Belgium, Swedish (n = 1916) and Italian (n = 497)) [258–260], but in not French and British studies. Study power and differences in risk allele frequency may contribute to the association differences. Interestingly, a smaller UK study (n = 50) focused on the extremes of the survival distribution (1.5%) and examined rare variants in UNC13A. Rare UNC13A variants were found exclusive to long and short survivors, however, this was not replicated in a larger Netherlands cohort [259]. Given that UNC13A is known to play a role in neurotransmission, larger population, and functional studies may help to determine if this locus could be a therapeutic target to slow ALS disease [316].
The Unc13A isoform is important for phasic release and olfactory memory formation at mushroom body synapses
Published in Journal of Neurogenetics, 2020
Jennifer Woitkuhn, Anatoli Ender, Christine B. Beuschel, Marta Maglione, Tanja Matkovic-Rachid, Sheng Huang, Martin Lehmann, Joerg R. P. Geiger, Stephan J. Sigrist
Functional organization of Kenyon cell output synapses remains insufficiently understood. Our analysis demonstrates that release factor Unc13A, consistent with its nanoscale positioning close to the active zone centre, is important for short-term plasticity and the phasic release component at Kenyon cell:MBON synapses. Notably, unc13A knockdown provoked a drastic deficit of aversive learning and memory, while Unc13B defects were milder. This finding implies a crucial role for the transmission of low frequency neuronal activity into information acquisition and encoding at MB output synapses. In the future, it will be highly relevant to directly study the role of Unc13A versus Unc13B mediated transmission during memory formation and storage.