Selective vulnerability in neurodegenerative diseases
Open accessAbstract
Neurodegenerative diseases have two general characteristics that are so fundamental we usually take them for granted. The first is that the pathology associated with the disease only affects particular neurons ('selective neuronal vulnerability'); the second is that the pathology worsens with time and impacts more regions in a stereotypical and predictable fashion. The mechanisms underpinning selective neuronal and regional vulnerability have been difficult to dissect, but the recent application of whole-genome technologies, the development of mouse models that reproduce spatial and temporal features of the pathology, and the identification of intrinsic morphological, electrophysiological, and biochemical properties of vulnerable neurons are beginning to shed some light on these fundamental features of neurodegenerative diseases. Here we detail our emerging understanding of the underlying biology of selective neuronal vulnerability and outline some of the areas in which our understanding is incomplete.
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Disease-associated genes are usually expressed by many CNS cell types, but select populations play an outsized role in driving disease progression.
“Disease-associated genes are usually expressed by many CNS cell types, but select populations play an outsized role in driving disease progression [48].”
From Elucidating brain transport pathways and cell type-dependent gene silencing of a durable lipid–siRNA conjugate administered into cerebrospinal fluid (2025) · cites this paper as [48]
The Abstract says disease-related proteins often have widespread expression while particular cell populations are selectively affected. The ‘Primary and secondary selective neuronal vulnerability’ section describes pathology arising in initially vulnerable cells and spreading to other regions. However, ‘Insight from genomics’ says many disease-associated loci are expressed in particular cell types; the paper does not establish that disease-associated genes are usually expressed across many CNS cell types. (LLM, conf=0.84)
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- Authors
- Fu, H., Hardy, J., & Duff, K. E.
- Affiliations
- Columbia University Irving Medical Center (US)
- UCL Queen Square Institute of Neurology (GB)
- Corresponding author
- Duff, Karen E.
- Venue
- Nature Neuroscience
- Published
- 2018-09-24
- Volume
- 21
- Issue
- 10
- Pages
- 1350-1358
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC6360529
- OpenAlex
- W2890004445
- Cited by
- 585
- References
- 154
- Citations by year
- 2026: 87 · 2025: 78 · 2024: 85 · 2023: 67 · 2022: 83 · 2021: 82 · 2020: 60 · 2019: 39 · 2018: 3
- FWCI
- 6.05
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- National Institute on Aging (RF1AG056151, K01AG056673)
- National Institute of Neurological Disorders and Stroke (R01NS074874)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- neurodegenerative diseases, selective neuronal vulnerability, regional vulnerability, disease progression
- MeSH terms
- Animals, Humans, Neurons, Neurodegenerative Diseases, Genome-Wide Association Study
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