Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways
Open accessAbstract
New players in Lou Gehrig's disease: Amyotrophic lateral sclerosis (ALS), often referred to as “Lou Gehrig's disease,” is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. Cirulli et al. sequenced the expressed genes of nearly 3000 ALS patients and compared them with those of more than 6000 controls (see the Perspective by Singleton and Traynor). They identified several proteins that were linked to disease in patients. One such protein, TBK1, is implicated in innate immunity and autophagy and may represent a therapeutic target. Science , this issue p. 1436 ; see also p. 1422
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Genetic studies provide evidence that defects in autophagy predispose to amyotrophic lateral sclerosis.
“genetic studies have provided evidence that defects in autophagy predispose to ALS (156, 157).”
From Microglia Function in the Central Nervous System During Health and Neurodegeneration (2017) · cites this paper as [156]
Neuropathological analysis of CNS tissue from ALS patients with TBK1 mutations shows SQSTM1- and TARDBP-positive inclusions in motor neurons and glia, along with reduced TBK1 mRNA and protein, suggesting haploinsufficiency mechanisms.
“Neuropathological analysis of CNS tissue from ALS patients with TBK1 mutations shows SQSTM1- and TARDBP-positive inclusions in motor neurons and glia [206,210,211], along with reduced TBK1 mRNA and protein, suggesting haploinsufficiency mechanisms [205,206].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [205]
TBK1 mutations are responsible for ~1% of patients with familial or otherwise sporadic ALS.
“Whole exome sequencing studies revealed that mutations in TBK1 are also responsible for ~1% of patients with familial or otherwise sporadic ALS [205,206].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [205]
ALS-associated mutations in TBK1, OPTN, SQSTM1, and VCP all affect autophagy as well as microglial function and innate immunity.
“ALS-associated mutations in TBK1, OPTN, SQSTM1, and VCP all affect autophagy as well as microglial function and innate immunity [192,205,206,441–443].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [205]
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BackgroundLoss of C9orf72 Enhances Autophagic Activity via Deregulated mTOR and TFEB Signaling
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“Although human genetics studies have revealed ALS-causing mutations in numerous genes that converge on the ALP (48, 49), the animals used in the present study have not been reported to display overt impairments in autophagy/lysosome function, likely due to the aggressive disease progression in…”
- Authors
- Cirulli, E. T., Lasseigne, B. N., Petrovski, S., Sapp, P. C., Dion, P. A., Leblond, C. S., Couthouis, J., Lu, Y.-F., Wang, Q., Krueger, B. J., Ren, Z., Keebler, J., Han, Y., Levy, S. E., Boone, B. E., Wimbish, J. R., Waite, L. L., Jones, A. L., Carulli, J. P., Day-Williams, A. G., Staropoli, J. F., Xin, W. W., Chesi, A., Raphael, A. R., McKenna-Yasek, D., Cady, J., Vianney de Jong, J. M. B., Kenna, K. P., Smith, B. N., Topp, S., Miller, J., Gkazi, A., FALS Sequencing Consortium, Al-Chalabi, A., van den Berg, L. H., Veldink, J., Silani, V., Ticozzi, N., Shaw, C. E., Baloh, R. H., Appel, S., Simpson, E., Lagier-Tourenne, C., Pulst, S. M., Gibson, S., Trojanowski, J. Q., Elman, L., McCluskey, L., Grossman, M., Shneider, N. A., Chung, W. K., Ravits, J. M., Glass, J. D., Sims, K. B., Van Deerlin, V. M., Maniatis, T., Hayes, S. D., Ordureau, A., Swarup, S., Landers, J., Baas, F., Allen, A. S., Bedlack, R. S., Harper, J. W., Gitler, A. D., Rouleau, G. A., Brown, R., Harms, M. B., Cooper, G. M., Harris, T., Myers, R. M., & Goldstein, D. B.
- Affiliations
- Duke University (US)
- HudsonAlpha Institute for Biotechnology (US)
- Columbia University (US)
- University of Massachusetts Chan Medical School (US)
- Montreal Neurological Institute and Hospital (CA)
- Stanford Medicine (US)
- Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA.
- Duke University School of Medicine, Durham, NC 27708, USA.
- Biogen (United States) (US)
- Biogen Idec, Cambridge, MA 02142, USA.
- Harvard University (US)
- Washington University in St. Louis (US)
- Department of Genome Analysis, Academic Medical Center, Meibergdreef 9, 1105AZ Amsterdam, Netherlands.
- Trinity College Dublin (IE)
- King's College London (GB)
- Department of Basic and Clinical Neuroscience, King’s College London, Institute of Psychiatry, Psychology and Neuroscience, London SE5 8AF, UK.
- Department of Neurology, Brain Center Rudolf Magnus, University Medical Centre Utrecht, 3508 GA Utrecht, Netherlands.
- University Medical Center Utrecht (NL)
- University of Milan (IT)
- Cedars-Sinai Medical Center (US)
- Houston Methodist (US)
- Ludwig Institute for Cancer Research and Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
- University of Utah (US)
- University of Pennsylvania (US)
- Columbia University Irving Medical Center (US)
- University of California San Diego (US)
- Emory University (US)
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
- Amsterdam UMC Location University of Amsterdam (NL)
- Durham VA Medical Center (US)
- Corresponding author
- Cirulli, Elizabeth T.
- Lasseigne, Brittany N.
- Harris, Tim
- Myers, Richard M.
- Goldstein, David B.
- ORCID
- Cirulli, Elizabeth T.
- Lasseigne, Brittany N.
- Petrovski, Slavé
- Dion, Patrick A.
- Leblond, Claire S.
- Couthouis, Julien
- Wang, Quanli
- Ren, Zhong
- Levy, Shawn E.
- Carulli, John P.
- Chesi, Alessandra
- Kenna, Kevin P.
- Smith, Bradley N.
- Topp, Simon
- Miller, Jack
- Veldink, Jan
- Silani, Vincenzo
- Ticozzi, Nicola
- Shaw, Christopher E.
- Baloh, Robert H.
- Appel, Stanley
- Pulst, Stefan M.
- Trojanowski, John Q.
- Elman, Lauren
- Grossman, Murray
- Shneider, Neil A.
- Chung, Wendy K.
- Ravits, John M.
- Sims, Katherine B.
- Maniatis, Tom
- Hayes, Sebastian D.
- Ordureau, Alban
- Swarup, Sharan
- Landers, John
- Baas, Frank
- Allen, Andrew S.
- Bedlack, Richard S.
- Harper, J. Wade
- Gitler, Aaron D.
- Rouleau, Guy A.
- Brown, Robert
- Harms, Matthew B.
- Cooper, Gregory M.
- Myers, Richard M.
- Goldstein, David B.
- Venue
- Science
- Published
- 2015-03-27
- Volume
- 347
- Issue
- 6229
- Pages
- 1436-1441
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC4437632
- OpenAlex
- W2061194981
- Cited by
- 966
- References
- 63
- Citations by year
- 2026: 34 · 2025: 53 · 2024: 66 · 2023: 62 · 2022: 75 · 2021: 82 · 2020: 107 · 2019: 94 · 2018: 110 · 2017: 107 · 2016: 114 · 2015: 62
- FWCI
- 92.36
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- ePrints Soton (University of Southampton) (acceptedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- eScholarship (California Digital Library) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion, other-oa)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Research Portal (Queen's University Belfast) (submittedVersion)
- Padua Research Archive (University of Padova) (submittedVersion)
- Funders
- Wellcome Trust (089701)
- National Institute for Health and Care Research (NF-SI-0512-10082)
- Motor Neurone Disease Association (TURNER/JAN13/944-795)
- National Institutes of Health (5ul1tr001067-05, TL1TR001066)
- Medical Research Council (MR/L021803/1, MC_G1000733, MR/L016397/1, MR/K01014X/1, MR/L501529/1)
- National Institute on Aging (P01AG017586, P50AG025688, P01AG032953)
- National Institute of General Medical Sciences (T32GM007754)
- National Institute of Neurological Disorders and Stroke (R01NS073873, K08NS075094, R37NS083524, R37NS033123)
- National Center for Advancing Translational Sciences (UL1-TR001067)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- amyotrophic lateral sclerosis, genetic risk factors, TBK1, optineurin, p62, autophagy, innate immunity, susceptibility genes, therapeutic target
- MeSH terms
- Sequestosome-1 Protein, Adolescent, Adult, Aged, Aged, 80 and over, Amyotrophic Lateral Sclerosis, Autophagy, Female, Genes, Humans, Male, Middle Aged, Protein Binding, Risk, Protein Serine-Threonine Kinases, Sequence Analysis, DNA, Cell Cycle Proteins, Genetic Predisposition to Disease, Membrane Transport Proteins, Transcription Factor TFIIIA, Adaptor Proteins, Signal Transducing, Young Adult, Genetic Association Studies, Exome
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