Rexach JE, Cheng Y, Chen L, Polioudakis D, Lin LC, Mitri V, Elkins A, Yin A, Calini D, Kawaguchi R, Ou J, Huang J, Williams C, Robinson J, Gaus SE, Spina S, Lee EB, Grinberg LT, Vinters H, Trojanowski JQ, Seeley WW, Malhotra D, Geschwind DH. Disease-specific selective vulnerability and neuroimmune pathways in dementia revealed by single cell genomics. bioRxiv. 2023 Sep 30; PubMed.
Recommends
Please login to recommend the paper.
Comments
University of California, San Francisco
Tau pathology is a common feature of several neurodegenerative diseases, but there are intriguing disease-specific differences: Each tauopathy is associated with a different spectrum of genetic risk factors, distinct cell types are affected, and recent cryo-EM structures have found different tau fibril conformations associated with different diseases. Therefore, an understanding of the molecular mechanisms that are common and distinct in different tauopathies is of great interest and therapeutic significance.
The new single-nucleus RNA sequencing and ATAC sequencing study by Jessica Rexach, Dan Geschwind and colleagues deeply profiles brain cells from patients with Alzheimer’s disease (AD), behavioral variant frontotemporal dementia (bvFTD), and progressive supranuclear palsy (PSP). Three brain regions with differential vulnerability to the different tauopathies were sampled and systematically compared.
Differentially expressed genes shared many commonalities across diseases, but AD microglia showed disease-specific signatures, which were associated with AD risk genes.
Intriguing new findings include the molecular description of selectively vulnerable neurons in PSP, which differ from previously described selectively vulnerable neuronal subtypes in AD and bvFTD. PSP-vulnerable neurons were enriched for the expression of several genes associated with PSP risk—recapitulating a theme previously observed in other diseases, such as Parkinson’s.
RORB, a marker previously described by us (Leng et al., 2021), was found to also mark vulnerable neurons in bvFTD. Rexach and colleagues map RORB targets that are differentially expressed in vulnerable neurons, which include the RORB-repressed synapse homeostasis gene NPTX2 and a cluster of stress response genes.
Furthermore, the authors found a decreased frequency of astrocytes in PSP, which could be due to cell death, or a change in cellular identity. The latter model is supported by the finding that astrocytes in PSP ectopically expressed neuronal transcription factors.
References:
Leng K, Li E, Eser R, Piergies A, Sit R, Tan M, Neff N, Li SH, Rodriguez RD, Suemoto CK, Leite RE, Ehrenberg AJ, Pasqualucci CA, Seeley WW, Spina S, Heinsen H, Grinberg LT, Kampmann M. Molecular characterization of selectively vulnerable neurons in Alzheimer's disease. Nat Neurosci. 2021 Feb;24(2):276-287. Epub 2021 Jan 11 PubMed.
View all comments by Martin KampmannVrije Universiteit Amsterdam
This manuscript is enormously important for understanding disease mechanisms in PSP and FTD. In Alzheimer’s, the identification of many genetic risk variants over the last decade had shown us the crucial involvement of lipid metabolism, immune dysfunction, and the endosomal system in this disease. Conversely, beyond the known tau variants themselves, we know very little about which biological processes contribute to disease in the much rarer pure tauopathies such as FTD and PSP. Similarly, single-nuclear RNA-Seq studies have helped tremendously to better understand AD, but similar studies for FTD and PSP are rare. This manuscript is therefore a milestone for these diseases and a treasure trove for the field.
Many interesting conclusions can be drawn from the data here. What I find most novel, and intriguing, is the discovery of unknown disease-specific pathways and vulnerabilities. In PSP, the authors discover a reduction in astrocyte number, a dysregulation of the astrocytic REST complex that controls astrocytic identify, and an upregulation of MAPT expression. This is a very important finding, as it may explain why tau pathology occurs in astrocytes in PSP patients.
In addition, cholesterol biosynthesis was among the significantly changed pathways in neurons in PSP patients. Even as a lipid aficionado, I had not expected that. In Alzheimer iPSC neurons, we have previously shown that cholesterol is a major regulator of tau levels, but in AD a link with cholesterol-transporting genes, such as ApoE, is easily made (van der Kant et al., 2019). This new data strengthens a link between cholesterol and tau also in pure tauopathies, and indicates that brain-cholesterol targeting interventions, such as low-dose efavirenz, might be clinically relevant for PSP as well (van der Kant et al., 2019).
The authors also implicate WNT signaling and synaptic vesicle cycles as major changed pathways in PSP, which should encourage much research into this novel direction.
It will be exciting to if see future functional studies validate the many findings in this paper. It is encouraging that the authors identify many pathways already known to be involved in AD (microglial changes) and in selective vulnerability (RORB). For FTD and PSP many of the findings are new, and I believe for these diseases this paper is a leap forward to understanding the underlying biology.
References:
van der Kant R, Langness VF, Herrera CM, Williams DA, Fong LK, Leestemaker Y, Steenvoorden E, Rynearson KD, Brouwers JF, Helms JB, Ovaa H, Giera M, Wagner SL, Bang AG, Goldstein LS. Cholesterol Metabolism Is a Druggable Axis that Independently Regulates Tau and Amyloid-β in iPSC-Derived Alzheimer's Disease Neurons. Cell Stem Cell. 2019 Mar 7;24(3):363-375.e9. Epub 2019 Jan 24 PubMed.
View all comments by Rik van der KantUniversity of Iowa
This intriguing work is, to the best of my knowledge, the largest PSP single-cell sequencing study to date and only the second overall (Sharma et al., 2021, was the first). I am fascinated by the finding that the REST complex is downregulated, because in our own recently published in vitro studies using human stem-cell derived astrocytes (Fiock et al., 2023), we found that several other regulators of astrocyte identity were downregulated in response to tau uptake.
The finding that tau is upregulated in PSP astrocytes highlights the need for further investigation, since both we (Fiock et al., 2023), and Dr. Kovac's group (Forrest et al., 2023) did not observe any change between diseases or between tau-positive and -negative astrocytes within PSP by RNAscope. Sharma et al. do not comment on such a change in their single-cell data (hopefully one of the authors will comment on this point).
I look forward to seeing both this work and Sharma et al. published and the corresponding datasets made publicly available as they will be an invaluable resource for the neurodegenerative disease research community.
References:
Fiock KL, Hook JN, Hefti MM. Determinants of astrocytic pathology in stem cell models of primary tauopathies. Acta Neuropathol Commun. 2023 Oct 6;11(1):161. PubMed.
Forrest SL, Lee S, Nassir N, Martinez-Valbuena I, Sackmann V, Li J, Ahmed A, Tartaglia MC, Ittner LM, Lang AE, Uddin M, Kovacs GG. Cell-specific MAPT gene expression is preserved in neuronal and glial tau cytopathologies in progressive supranuclear palsy. Acta Neuropathol. 2023 Sep;146(3):395-414. Epub 2023 Jun 24 PubMed.
Sharma A, Song W-M, Farrell K, Whitney K, Zhang B, Crary JF, Pereira AC. Single-cell atlas of progressive supranuclear palsy reveals a distinct hybrid glial cell population. 2021 Apr 12 10.1101/2021.04.11.439393 (version 1) bioRxiv.
View all comments by Marco HeftiMake a Comment
To make a comment you must login or register.