Kaivola K, Chia R, Ding J, Rasheed M, Fujita M, Menon V, Walton RL, Collins RL, Billingsley K, Brand H, Talkowski M, Zhao X, Dewan R, Stark A, Ray A, Solaiman S, Alvarez Jerez P, Malik L, Dawson TM, Rosenthal LS, Albert MS, Pletnikova O, Troncoso JC, Masellis M, Keith J, Black SE, Ferrucci L, Resnick SM, Tanaka T. Genome-wide structural variant analysis identifies risk loci for non-Alzheimer’s dementias. https://doi.org/10.1016/j.xgen.2023.100316 Cell Genomics

Recommends

Please login to recommend the paper.

Comments

  1. The main takeaway from this study is the identification and characterization of structural variants in non-Alzheimer's dementias, specifically Lewy body dementia (LBD) and frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS). By applying a multi-algorithm pipeline (GATK-SV) to short-read whole-genome sequence data, the researchers were able to identify a novel risk locus for LBD, a deletion in TPCN1, and confirm known structural variants at the C9ORF72 and MAPT loci associated with FTD/ALS. They also discovered rare pathogenic structural variants in both LBD and FTD/ALS.

    One surprising finding was the association of a 309-base-pair deletion in TPCN1 with LBD. TPCN1 encodes an ion channel expressed in neuronal and glial endo-lysosomal membranes. This deletion may have potential implications for Alzheimer's disease, as a suggestive association between the intronic TPCN1 variant rs6489896 and Alzheimer's disease was reported in a recent GWAS. The TPCN1 locus did not correlate with Parkinson's disease, indicating that the deletion might not be specific to LBD. The study also identified rare structural variants in neurodegenerative disease genes, such as SNCA duplications in Parkinson's disease and LBD, and OPTN deletions in FTD and ALS.

    The results of this study highlight the value of studying structural variants in understanding the underlying pathogenesis of non-Alzheimer's dementia. The researchers have also provided an interactive resource that can be investigated by other researchers for new insights into these dementias. However, there are limitations to the study, stemming from the inherent difficulty of calling structural variants from short-read whole-genome sequencing data. Despite these challenges, this study demonstrates the utility of using short-read whole-genome sequencing for structural variant discovery and sheds light on the role of structural variants in non-Alzheimer's dementias.

    View all comments by Vivek Swarup

  2. This is a very interesting finding, though I’ll note that TPC1 two-pore channels are not voltage-gated calcium channels; the reference [34] in the paper is outdated. Rather, they are PI(3,5)P2-activated Na+ channels that function mainly in endosomes, see ref [37] in the paper and see also a more recent review article that describes their function (Wang et al., 2023). 

    Overall, these genetic findings further support the importance of the endosomal/lysosomal system in neurodegeneration. The likely mechanism is related to autophagic defects. We recently published a connection between dysregulated calcium signaling and autophagy defects in AD as discussed on Alzforum (Mar 2023 news). 

    In the case of Lewy body dementia and frontotemporal dementia/amyotrophic lateral sclerosis examined by Kaivola, their discovery of the TPC1 locus points to a more direct connection with dysfunction of the endosomal/lysosomal/autophagy pathway.

    References:

    Wang Q, Zhu MX. NAADP-Dependent TPC Current. Handb Exp Pharmacol. 2023;278:35-56. PubMed.

    View all comments by Ilya Bezprozvanny

  3. This is exciting work that continues to show endo-lysosomal deficits in neurodegenerative diseases and serves as a common mechanistic link between shared phenotypes in LBD and AD. TPCN1 encodes the two-pore channels (TPC) which are present on endo-lysosomal vesicles. Release of Ca2+ from lysosomal stores via TPC channels plays a role in autophagy-degradation, lysosomal acidification and proteolysis, vesicle fusion, etc., all of which are important in reducing misfolded and damaged proteins.

    In LBD, the deletion of TPCN1 would therefore likely have downstream consequences on protein clearance and increased cellular stress. Recent work by Tong et al., 2022, claimed that inhibition of TPC in cells expressing mutant PSEN1 restored the reduced lysosomal Ca2+ release and acidified lysosomes, thereby rescuing autophagy. This work was similar to that of Ralph Nixon’s group (Lee et al., 2010, 2015) where they showed that regulating the hyperactive TRPML1 (another lysosomal Ca2+ efflux channel) restored lysosomal acidic pH and calcium release, as well as autophagic clearance. Therefore, TPC loss can disrupt calcium and proton balance, the electrochemical gradient of the lysosomes, and its downstream function.

    Other channels, including the vacuolar-ATPase (vATPase), maintain this gradient as well. Cytosolic rise in Ca2+ concentrations is present in early stages of Alzheimer’s and disrupts the vATPase function and lysosomal acidification (Mustaly-Kalimi et al., 2022), which can have downstream effects on TPC and lysosomal Ca2+ regulation.

    In this paper, the authors also suggested that TPCN1 deletion could disrupt RITA1 and notch signaling. This is interesting, as disruption in notch signaling is thought to play a role in vascular damage in AD. Therefore, there is a  possible link between endo-lysosomal disruption and neurovascular-related dementia (Kapoor and Nation, 2020). 

    References:

    Kapoor A, Nation DA. Role of Notch signaling in neurovascular aging and Alzheimer's disease. Semin Cell Dev Biol. 2020 Dec 28; PubMed.

    Lee JH, McBrayer MK, Wolfe DM, Haslett LJ, Kumar A, Sato Y, Lie PP, Mohan P, Coffey EE, Kompella U, Mitchell CH, Lloyd-Evans E, Nixon RA. Presenilin 1 Maintains Lysosomal Ca(2+) Homeostasis via TRPML1 by Regulating vATPase-Mediated Lysosome Acidification. Cell Rep. 2015 Sep 1;12(9):1430-44. Epub 2015 Aug 20 PubMed.

    Lee JH, Yu WH, Kumar A, Lee S, Mohan PS, Peterhoff CM, Wolfe DM, Martinez-Vicente M, Massey AC, Sovak G, Uchiyama Y, Westaway D, Cuervo AM, Nixon RA. Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell. 2010 Jun 25;141(7):1146-58. PubMed.

    Mustaly-Kalimi S, Gallegos W, Marr RA, Gilman-Sachs A, Peterson DA, Sekler I, Stutzmann GE. Protein mishandling and impaired lysosomal proteolysis generated through calcium dysregulation in Alzheimer's disease. Proc Natl Acad Sci U S A. 2022 Dec 6;119(49):e2211999119. Epub 2022 Nov 28 PubMed.

    Tong BC, Wu AJ, Huang AS, Dong R, Malampati S, Iyaswamy A, Krishnamoorthi S, Sreenivasmurthy SG, Zhu Z, Su C, Liu J, Song J, Lu JH, Tan J, Pan W, Li M, Cheung KH. Lysosomal TPCN (two pore segment channel) inhibition ameliorates beta-amyloid pathology and mitigates memory impairment in Alzheimer disease. Autophagy. 2021 Jul 27;:1-19. PubMed.

    View all comments by Grace Stutzmann

Make a Comment

To make a comment you must login or register.

This paper appears in the following:

News

  1. Whole Genome Analysis Nets New Lewy Body Dementia Gene