Latest articles published on Science Advances

This week, we would like to share several latest articles published on Science Advances.

Title: Misexpression of genes lacking CpG islands drives degenerative changes during aging
Authors: Jun-Yeong Lee, Ian Davis, Elliot H. H. Youth, Jonghwan Kim, Gary Churchill, James Godwin, Ron Korstanje, Samuel Beck
Type: Research Article of Science Advances
Abstract:
Cellular aging is characterized by disruption of the nuclear lamina and its associated heterochromatin. How these structural changes within the nucleus contribute to age-related degeneration of the organism is unclear. Genes lacking CpG islands (CGI⁻ genes) generally associate with heterochromatin when they are inactive. Here, we show that the expression of these genes is globally activated in aged cells and tissues. This CGI⁻ gene misexpression is a common feature of normal and pathological aging in mice and humans. We report evidence that CGI⁻ gene up-regulation is directly responsible for age-related physiological deterioration, notably for increased secretion of inflammatory mediators.
Access this article: https://www.science.org/doi/10.1126/sciadv.abj9111

Title: Deletion of Abi3 gene locus exacerbates neuropathological features of Alzheimer’s disease in a mouse model of Aβ amyloidosis
Authors: Hande Karahan, Daniel C. Smith, Byungwook Kim, Luke C. Dabin, MD Mamun Al-Amin, H. R. Sagara Wijeratne, Taylor Pennington, Gonzalo Viana Di Prisco, Brianne Mccord, Peter Bor-Chian Lin, Yuxin Li, Junmin Peng, Adrian L. Oblak, Shaoyou Chu, Brady K. Atwood, Jungsu Kim
Type: Research Article of Science Advances
Abstract:
Recently, large-scale human genetics studies identified a rare coding variant in the ABI3 gene that is associated with an increased risk of Alzheimer’s disease (AD). However, pathways by which ABI3 contributes to the pathogenesis of AD are unknown. To address this question, we determined whether loss of ABI3 function affects pathological features of AD in the 5XFAD mouse model. We demonstrate that the deletion of Abi3 locus significantly increases amyloid β (Aβ) accumulation and decreases microglia clustering around the plaques. Furthermore, long-term potentiation is impaired in 5XFAD; Abi3 knockout ("Abi3^−/−") mice. Moreover, we identified marked changes in the proportion of microglia subpopulations in Abi3^−/− mice using a single-cell RNA sequencing approach. Mechanistic studies demonstrate that Abi3 knockdown in microglia impairs migration and phagocytosis. Together, our study provides the first in vivo functional evidence that loss of ABI3 function may increase the risk of developing AD by affecting Aβ accumulation and neuroinflammation. 
Access this article: https://www.science.org/doi/10.1126/sciadv.abe3954

Title: In vivo rate-determining steps of tau seed accumulation in Alzheimer's disease
Authors: Georg Meisl, Eric Hidari, Kieren Allinson, Timothy Rittman, Sarah L. Devos, Justin S. Sanchez, Catherine K. Xu, Karen E. Duff, Keith A. Johnson, James B. Rowe, Bradley T. Hyman, Tuomas P. J. Knowles, David Klenerman
Type: Research Article of Science Advances
Abstract:
Both the replication of protein aggregates and their spreading throughout the brain are implicated in the progression of Alzheimer’s disease (AD). However, the rates of these processes are unknown and the identity of the rate-determining process in humans has therefore remained elusive. By bringing together chemical kinetics with measurements of tau seeds and aggregates across brain regions, we can quantify their replication rate in human brains. Notably, we obtain comparable rates in several different datasets, with five different methods of tau quantification, from postmortem seed amplification assays to tau PET studies in living individuals. Our results suggest that from Braak stage III onward, local replication, rather than spreading between brain regions, is the main process controlling the overall rate of accumulation of tau in neocortical regions. The number of seeds doubles only every~5 years. Thus, limiting local replication likely constitutes the most promising strategy to control tau accumulation during AD.
Access this article: https://www.science.org/doi/10.1126/sciadv.abh1448

Title: Neurodegenerative processes accelerated by protein malnutrition and decelerated by essential amino acids in a tauopathy mouse model
Authors: Hideaki Sato,Yuhei Takado, Sakiko Toyoda, Masako Tsukamoto-Yasui, Keiichiro Minatohara, Hiroyuki Takuwa, Takuya Urushihata, Manami Takahashi, Masafumi Shimojo, Maiko Ono, Jun Maeda, Asumi Orihara, Naruhiko Sahara, Ichio Aoki, Sachise Karakawa, Muneki Isokawa, Noriko Kawasaki, Mika Kawasaki, Satoko Ueno, Mayuka Kanda, Mai Nishimura, Katsuya Suzuki, Akira Mitsui, Kenji Nagao, Akihiko Kitamura, Makoto Higuchi
Type: Research Article of Science Advances
Abstract:
Protein malnutrition is epidemiologically suggested as a potential risk factor for senile dementia, although molecular mechanisms linking dietary proteins and amino acids to neurodegeneration remain unknown. Here, we show that a low-protein diet resulted in down-regulated expression of synaptic components and a modest acceleration of brain atrophy in mice modeling neurodegenerative tauopathies. Notably, these abnormal phenotypes were robustly rescued by the administration of seven selected essential amino acids. The up-regulation of inflammation-associated gene expression and progressive brain atrophy in the tauopathy model were profoundly suppressed by treatment with these essential amino acids without modifications of tau depositions. Moreover, the levels of kynurenine, an initiator of a pathway inducing neuroinflammatory gliosis and neurotoxicity in the brain, were lowered by treatment through inhibition of kynurenine uptake in the brain. Our findings highlight the importance of specific amino acids as systemic mediators of brain homeostasis against neurodegenerative processes.
Access this article: https://www.science.org/doi/10.1126/sciadv.abd5046

Title: Global ubiquitylation analysis of mitochondria in primary neurons identifies endogenous Parkin targets following activation of PINK1
Authors: Odetta Antico, Alban Ordureau, Michael Stevens, Francois Singh, Raja S. Nirujogi, Marek Gierlinski, Erica Barini, Mollie L. Rickwood, Alan Prescott, Rachel Toth, Ian G. Ganley, J. Wade Harper, Miratul M. K. Muqit
Type: Research Resource of Science Advances
Abstract:
How activation of PINK1 and Parkin leads to elimination of damaged mitochondria by mitophagy is largely based on cell lines with few studies in neurons. Here, we have undertaken proteomic analysis of mitochondria from mouse neurons to identify ubiquitylated substrates of endogenous Parkin. Comparative analysis with human iNeuron datasets revealed a subset of 49 PINK1 activation–dependent diGLY sites in 22 proteins conserved across mouse and human systems. We use reconstitution assays to demonstrate direct ubiquitylation by Parkin in vitro. We also identified a subset of cytoplasmic proteins recruited to mitochondria that undergo PINK1 and Parkin independent ubiquitylation, indicating the presence of alternate ubiquitin E3 ligase pathways that are activated by mitochondrial depolarization in neurons. Last, we have developed an online resource to search for ubiquitin sites and enzymes in mitochondria of neurons, MitoNUb. These findings will aid future studies to understand Parkin activation in neuronal subtypes.
Access this article: https://www.science.org/doi/10.1126/sciadv.abj0722

Title: The PET tracer [¹¹C]MK-6884 quantifies M4 muscarinic receptor in rhesus monkeys and patients with Alzheimer’s disease
Authors: Wenping Li, Yuchuan Wang, Talakad G. Lohith, Zhizhen Zeng, Ling Tong, Robert Mazzola, Kerry Riffel, Patricia Miller, Mona Purcell, Marie Holahan, Hyking Haley, Liza Gantert, David Hesk, Sumei Ren, John Morrow, Jason Uslaner, Arie Struyk, Jenny Miu-Chun Wai, Michael T. Rudd, David M. Tellers, Thomas Mcavoy, Guy Bormans, Michel Koole, Koen Van Laere, Kim Serdons, Jan De Hoon, Ruben Declercq, Inge De Lepeleire, Maria B. Pascual, Paolo Zanotti-Fregonara, Meixiang Yu, Victoria Arbones, Joseph C. Masdeu, Amy Cheng, Azher Hussain, Tjerk Bueters, Matt S. Anderson, Eric D. Hostetler, Anthony S. Basile
Type: Research Article of Science Advances
Abstract:
Activation of the M4 muscarinic receptor (M4R) might be therapeutic in patients with Alzheimer’s disease (AD). However, the development of selective agonists is hindered by the lack of in vivo methods to measure target engagement. Now, Li et al. developed a positron emission tomography (PET) tracer called [¹¹C]MK-6884 able to bind an allosteric site of M4R with high selectivity. Characterization of the tracer in monkeys, healthy human volunteers, and patients with AD showed selective target engagement and sensitivity to the orthosteric M4R agonist carbachol in vitro and to the acetylcholinesterase inhibitor donepezil in vivo in monkeys and healthy human volunteers. The results suggest that [¹¹C]MK-6884 could be used to measure target engagement in clinical trials and drug development.
Access this article: https://www.science.org/doi/10.1126/scitranslmed.abg3684