Our staff editors continue to share exciting, interesting, and thought-provoking reading material in the recommended articles series.
This week, we would like to share several latest articles on neurodegenerative diseases.
Title: Involvement of neuronal and muscular Trk-fused gene (TFG) defects in the development of neurodegenerative diseases
Authors: Takeshi Yamamotoya, Shun Hasei, Yasuyuki Akasaka, Yukino Ohata, Yusuke Nakatsu, Machi Kanna, Midori Fujishiro, Hideyuki Sakoda, Hiraku Ono, Akifumi Kushiyama, Hidemi Misawa, Tomoichiro Asano
Type: Article of Scientific Reports
Trk-fused gene (TFG) mutations have been identified in patients with several neurodegenerative diseases. In this study, we attempted to clarify the effects of TFG deletions in motor neurons and in muscle fibers, using tissue-specific TFG knockout (vMNTFG KO and MUSTFG KO) mice. vMNTFG KO, generated by crossing TFG floxed with VAChT-Cre, showed deterioration of motor function and muscle atrophy especially in slow-twitch soleus muscle, in line with the predominant Cre expression in slow-twitch fatigue-resistant (S) and fast-twitch fatigue-resistant (FR) motor neurons. Consistently, denervation of the neuromuscular junction (NMJ) was apparent in the soleus, but not in the extensor digitorum longus, muscle. Muscle TFG expressions were significantly downregulated in vMNTFG KO, presumably due to decreased muscle IGF-1 concentrations. However, interestingly, MUSTFG KO mice showed no apparent impairment of muscle movements, though a denervation marker, AChRγ, was elevated and Agrin-induced AChR clustering in C2C12 myotubes was inhibited. Our results clarify that loss of motor neuron TFG is sufficient for the occurrence of NMJ degeneration and muscle atrophy, though lack of muscle TFG may exert an additional effect. Reduced muscle TFG, also observed in aged mice, might be involved in age-related NMJ degeneration, and this issue merits further study.
Access this article: https://doi.org/10.1038/s41598-022-05884-7
Title: Oligonucleotide correction of an intronic TIMMDC1 variant in cells of patients with severe neurodegenerative disorder
Authors: Raman Kumar, Mark A. Corbett, Nicholas J. C. Smith, Daniella H. Hock, Zoya Kikhtyak, Liana N. Semcesen, Atsushi Morimoto, Sangmoon Lee, David A. Stroud, Joseph G. Gleeson, Eric A. Haan, Jozef Gecz
Type: Article of npj Genomic Medicine
TIMMDC1 encodes the Translocase of Inner Mitochondrial Membrane Domain-Containing protein 1 (TIMMDC1) subunit of complex I of the electron transport chain responsible for ATP production. We studied a consanguineous family with two affected children, now deceased, who presented with failure to thrive in the early postnatal period, poor feeding, hypotonia, peripheral neuropathy and drug-resistant epilepsy. Genome sequencing data revealed a known, deep intronic pathogenic variant TIMMDC1 c.597-1340A>G, also present in gnomAD (~1/5000 frequency), that enhances aberrant splicing. Using RNA and protein analysis we show almost complete loss of TIMMDC1 protein and compromised mitochondrial complex I function. We have designed and applied two different splice-switching antisense oligonucleotides (SSO) to restore normal TIMMDC1 mRNA processing and protein levels in patients’ cells. Quantitative proteomics and real-time metabolic analysis of mitochondrial function on patient fibroblasts treated with SSOs showed restoration of complex I subunit abundance and function. SSO-mediated therapy of this inevitably fatal TIMMDC1 neurologic disorder is an attractive possibility.
Access this article: https://doi.org/10.1038/s41525-021-00277-7
Title: Deep phenotyping of Alzheimer's disease leveraging electronic medical records identifies sex-specific clinical associations
Authors: Alice S. Tang, Tomiko Oskotsky, Shreyas Havaldar, William G. Mantyh, Mesude Bicak, Caroline Warly Solsberg, Sarah Woldemariam, Billy Zeng, Zicheng Hu, Boris Oskotsky, Dena Dubal, Isabel E. Allen, Benjamin S. Glicksberg, Marina Sirota
Type: Article of Nature Communications
Alzheimer’s Disease (AD) is a neurodegenerative disorder that is still not fully understood. Sex modifies AD vulnerability, but the reasons for this are largely unknown. We utilize two independent electronic medical record (EMR) systems across 44,288 patients to perform deep clinical phenotyping and network analysis to gain insight into clinical characteristics and sex-specific clinical associations in AD. Embeddings and network representation of patient diagnoses demonstrate greater comorbidity interactions in AD in comparison to matched controls. Enrichment analysis identifies multiple known and new diagnostic, medication, and lab result associations across the whole cohort and in a sex-stratified analysis. With this data-driven method of phenotyping, we can represent AD complexity and generate hypotheses of clinical factors that can be followed-up for further diagnostic and predictive analyses, mechanistic understanding, or drug repurposing and therapeutic approaches.
Access this article: https://doi.org/10.1038/s41467-022-28273-0
Title: A combination of multiple autoantibodies is associated with the risk of Alzheimer's disease and cognitive impairment
Authors: Sung-Mi Shim, Young Ho Koh, Jong-Hoon Kim, Jae-Pil Jeon
Type: Article of Scientific Reports
Autoantibodies are self-antigen reactive antibodies that play diverse roles in the normal immune system, tissue homeostasis, and autoimmune and neurodegenerative diseases. Anti-neuronal autoantibodies have been detected in neurodegenerative disease serum, with unclear significance. To identify diagnostic biomarkers of Alzheimer’s disease (AD), we analyzed serum autoantibody profiles of the HuProt proteome microarray using the discovery set of cognitively normal control (NC, n = 5) and AD (n = 5) subjects. Approximately 1.5-fold higher numbers of autoantibodies were detected in the AD group (98.0 ± 39.9/person) than the NC group (66.0 ± 39.6/person). Of the autoantigen candidates detected in the HuProt microarray, five autoantigens were finally selected for the ELISA-based validation experiment using the validation set including age- and gender-matched normal (NC, n = 44), mild cognitive impairment (MCI, n = 44) and AD (n = 44) subjects. The serum levels of four autoantibodies including anti-ATCAY, HIST1H3F, NME7 and PAIP2 IgG were significantly different among NC, MCI and/or AD groups. Specifically, the anti-ATCAY autoantibody level was significantly higher in the AD (p = 0.003) and MCI (p = 0.015) groups compared to the NC group. The anti-ATCAY autoantibody level was also significantly correlated with neuropsychological scores of MMSE (rs = − 0.229, p = 0.012), K-MoCA (rs = − 0.270, p = 0.003), and CDR scores (rs = 0.218, p = 0.016). In addition, a single or combined occurrence frequency of anti-ATCAY and anti-PAIP2 autoantibodies was significantly associated with the risk of MCI and AD. This study indicates that anti-ATCAY and anti-PAIP2 autoantibodies could be a potential diagnostic biomarker of AD.
Access this article: https://doi.org/10.1038/s41598-021-04556-2
Title: The mouse metallomic landscape of aging and metabolism
Authors: Jean-David Morel, Lucie Sauzéat, Ludger J. E. Goeminne, Pooja Jha, Evan Williams, Riekelt H. Houtkooper, Ruedi Aebersold, Johan Auwerx, Vincent Balter
Type: Article of Nature Communications
Organic elements make up 99% of an organism but without the remaining inorganic bioessential elements, termed the metallome, no life could be possible. The metallome is involved in all aspects of life, including charge balance and electrolytic activity, structure and conformation, signaling, acid-base buffering, electron and chemical group transfer, redox catalysis energy storage and biomineralization. Here, we report the evolution with age of the metallome and copper and zinc isotope compositions in five mouse organs. The aging metallome shows a conserved and reproducible fingerprint. By analyzing the metallome in tandem with the phenome, metabolome and proteome, we show networks of interactions that are organ-specific, age-dependent, isotopically-typified and that are associated with a wealth of clinical and molecular traits. We report that the copper isotope composition in liver is age-dependent, extending the existence of aging isotopic clocks beyond bulk organic elements. Furthermore, iron concentration and copper isotope composition relate to predictors of metabolic health, such as body fat percentage and maximum running capacity at the physiological level, and adipogenesis and OXPHOS at the biochemical level. Our results shed light on the metallome as an overlooked omic layer and open perspectives for potentially modulating cellular processes using careful and selective metallome manipulation.
Access this article: https://doi.org/10.1038/s41467-022-28060-x
Title: Senescence and impaired DNA damage responses in alpha-synucleinopathy models
Authors: Ye-Seul Yoon, Jueng Soo You, Tae-Kyung Kim, Woo Jung Ahn, Myoung Jun Kim, Keun Hong Son, Diadem Ricarte, Darlene Ortiz, Seung-Jae Lee, He-Jin Lee
Type: Article of Experimental & Molecular Medicine
α-Synuclein is a crucial element in the pathogenesis of Parkinson’s disease (PD) and related neurological diseases. Although numerous studies have presented potential mechanisms underlying its pathogenesis, the understanding of α-synuclein-mediated neurodegeneration remains far from complete. Here, we show that overexpression of α-synuclein leads to impaired DNA repair and cellular senescence. Transcriptome analysis showed that α-synuclein overexpression led to cellular senescence with activation of the p53 pathway and DNA damage responses (DDRs). Chromatin immunoprecipitation analyses using p53 and γH2AX, chromosomal markers of DNA damage, revealed that these proteins bind to promoters and regulate the expression of DDR and cellular senescence genes. Cellular marker analyses confirmed cellular senescence and the accumulation of DNA double-strand breaks. The non-homologous end joining (NHEJ) DNA repair pathway was activated in α-synuclein-overexpressing cells. However, the expression of MRE11, a key component of the DSB repair system, was reduced, suggesting that the repair pathway induction was incomplete. Neuropathological examination of α-synuclein transgenic mice showed increased levels of phospho-α-synuclein and DNA double-strand breaks, as well as markers of cellular senescence, at an early, presymptomatic stage. These results suggest that the accumulation of DNA double-strand breaks (DSBs) and cellular senescence are intermediaries of α-synuclein-induced pathogenesis in PD.
Access this article: https://doi.org/10.1038/s12276-022-00727-x