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Molecular and cellular mechanisms of selective vulnerability in neurodegenerative diseases

Nature Reviews Neuroscience volume 25, pages 351–371 (2024)Cite this article

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Abstract

The selective vulnerability of specific neuronal subtypes is a hallmark of neurodegenerative diseases. In this Review, I summarize our current understanding of the brain regions and cell types that are selectively vulnerable in different neurodegenerative diseases and describe the proposed underlying cell-autonomous and non-cell-autonomous mechanisms. I highlight how recent methodological innovations — including single-cell transcriptomics, CRISPR-based screens and human cell-based models of disease — are enabling new breakthroughs in our understanding of selective vulnerability. An understanding of the molecular mechanisms that determine selective vulnerability and resilience would shed light on the key processes that drive neurodegeneration and point to potential therapeutic strategies to protect vulnerable cell populations.

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Fig. 1: Overview of brain regions and cell populations that are selectively vulnerable in neurodegenerative diseases.
Fig. 2: From differentially expressed genes to mechanisms of selective vulnerability.
Fig. 3: Cell-autonomous mechanisms of selective vulnerability.
Fig. 4: Non-cell-autonomous mechanisms of selective vulnerability.

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Acknowledgements

The author thanks S. Kaufman for the early discussions and S. Kaufman, B. Ramani and D. Mordes for feedback on parts of the manuscript. Research into selective vulnerability in neurodegenerative diseases in the Kampmann lab is supported by National Institutes of Health/National Institute on Aging grant R01 AG082141, a Ben Barres Early Career Acceleration Award from the Chan Zuckerberg Initiative, the Tau Consortium, the National Institute of Neurological Disorders and Stroke (NINDS) Center Without Walls (NIH/NINDS U54 NS123746), and the University of California, San Francisco/University of California, Berkeley Innovative Genomics Institute (IGI).

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  1. Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA

    Martin Kampmann

  2. Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA, USA

    Martin Kampmann

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  1. Martin Kampmann
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Correspondence to Martin Kampmann.

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Competing interests

M.K. is a co-scientific founder of Montara Therapeutics and serves on the Scientific Advisory Boards of Engine Biosciences, Casma Therapeutics, Cajal Neuroscience, and Alector, and is an adviser to Modulo Bio and Recursion Therapeutics. M.K. is an inventor on US Patent 11,254,933 related to CRISPRi and CRISPRa screening, and on a US Patent application on in vivo screening methods.

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Nature Reviews Neuroscience thanks Tracy Young-Pearse, who co-reviewed with Sarah Heuer; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Autophagy

A process that targets cellular components, including protein aggregates and organelles, for lysosomal degradation.

Calcium-buffering proteins

Proteins that bind and, thereby, regulate levels of calcium ions within cells, preventing excessive calcium-induced cellular damage.

CRISPR

The CRISPR (clustered regularly interspaced short palindromic repeats)–Cas (CRISPR-associated proteins) system is a bacterial anti-viral defence mechanism that has been adapted for gene editing and gene regulation purposes in human cells and many other biological systems.

Cryo-electron microscopy

(Cryo-EM). A technique that allows the visualization of biological molecules and structures at near-atomic resolution after rapid freezing of samples without the need for chemical fixation or staining.

Excitotoxicity

A process that results from excessive activation of excitatory neurotransmitter receptors, particularly glutamate receptors, which increases intracellular calcium concentrations in neurons and leads to neuronal damage or death.

Genetic risk factors

Variants in the genome sequence of an individual that increase their likelihood of developing a particular disease.

Genome-wide association studies

(GWAS). Studies that analyse genetic variants across the entire genome to identify associations between specific genetic variants and traits such as disease risk.

Immunohistochemistry

A technique that uses antibodies against proteins of interest to visualize their levels and localization in fixed tissue samples.

Induced pluripotent stem cell

(iPSC). Cells that are derived from somatic cells, such as blood cells or skin fibroblasts, and reprogrammed by the expression of a combination of genes to regain the ability to differentiate into various cell types.

Molecular chaperones

Proteins that facilitate the proper folding and assembly of other proteins, thereby preventing protein misfolding and aggregation.

Oxidative stress

Stress experienced by cells when they are exposed to excessive levels of reactive oxygen species.

Patch sequencing

(Patch-seq). A technique that combines whole-cell patch clamp recording with single-cell RNA sequencing, allowing the simultaneous measurement of electrical activity and gene expression in individual neurons.

Proteostasis

Short for protein homoeostasis, describes the proper balance of protein synthesis, folding and degradation; its disruption can lead to protein misfolding, aggregation and toxic consequences.

Reactive oxygen species

(ROS). Highly reactive molecules containing oxygen atoms, which are generated as byproducts of normal cellular metabolism and can cause oxidative damage to biomolecules when present in excessive amounts.

Single-nucleus RNA sequencing

(snRNA-seq). A molecular technique used to analyse gene expression profiles at the single-cell level by sequencing RNA extracted from individual cell nuclei.

Spatial transcriptomics

A technique that quantifies large numbers of transcript levels within tissue sections while preserving spatial information, allowing for the mapping of gene expression profiles to specific regions and cells.

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Kampmann, M. Molecular and cellular mechanisms of selective vulnerability in neurodegenerative diseases. Nat. Rev. Neurosci. 25, 351–371 (2024). https://doi.org/10.1038/s41583-024-00806-0

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