| ALS and frontotemporal dementia | Rare Neurological Diseases  

Single-cell dissection of the human motor and prefrontal cortices in ALS and FTLD

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) show similarities in pathology and genetics, hinting at shared disease mechanisms. Pineda et al. used single-nucleus RNA sequencing to study vulnerabilities, revealing common gene dysregulation. C9orf72 mutation may precede transcriptional changes, with NEFL upregulation possibly compensating for axonal damage. Additionally, they observed problems with blood vessels in the brain and changes in how the immune system works. This research connects vulnerable cell types in ALS and FTLD, offering insights into disease understanding and potential treatments.

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) share clinical, pathological, and genetic features1, suggesting they belong to the same disease spectrum. Pathologically, both exhibit TDP-43 pathology2, with common genetic mutations like the C9orf72 hexanucleotide repeat expansion. Cell-type vulnerabilities in ALS and FTLD involve upper and lower motor neurons (UMNs and LMNs) and specific cortical neurons, such as Betz cells in the primary motor cortex (MCX) for ALS and von Economo neurons (VENs) in the dorsolateral prefrontal cortex (PFC) for FTLD.
In the present study Pineda et al.3, in order to study the above-mentioned vulnerabilities, employed single-nucleus RNA sequencing (snRNA-seq) on brain tissues from ALS, FTLD, and control patients, identifying and characterizing vulnerable cell populations, examining transcriptional alterations, and elucidating disease mechanisms across cell types and brain regions. This approach sheds light on the molecular underpinnings of cell-specific vulnerability in ALS and FTLD.
Authors observed the conservation of cell-type-specific gene dysregulation in ALS and FTLD, with significant similarity between sporadic and familial (C9) cases. This suggests that C9orf72 G4C2-mediated toxicity likely precedes most disease-associated transcriptional changes. NEFL, an ALS-linked protein, showed robust upregulation across cell types, potentially reflecting a compensatory response to axonal degradation. They also observed cerebrovascular impairment and homeostatic dysregulation, along with altered NK cell activity. Differentially vulnerable cell populations converged with population-level genetic risk factors and transcriptional dysregulation, notably motor and spindle neuron populations. The vulnerability signature included enrichment of ALS- and FTLD-linked genes, as well as primary cilia and axoneme-related genes, suggesting an unexplored determinant of vulnerability. Furthermore, they identified a susceptible translaminar L2-5 pyramidal neurons SCN4B+, an excitatory neuron population in the MCX, sharing molecular characteristics with UMNs and spindle neurons. UMNs and spindle neurons in the MCX and PFC belong to a larger population of L5 VAT1L+ neuron population, depleted in ALS and FTLD, expanding potential therapeutic targets. Stereological analysis revealed susceptibility granularity, with Betz cells exhibiting more extensive loss than non-Betz counterparts.
In conclusion, molecular identity serves as a criterion for classifying vulnerable cell types in ALS and FTLD, establishing a transcriptional link between distinct susceptible populations across the nervous system and the ALS-FTLD pathological spectrum.

Key Points:

  • Shared Features: ALS and FTLD share clinical, pathological, and genetic characteristics, indicating they are part of the same disease spectrum, with common TDP-43 pathology and C9orf72 mutations.
  • Cell-Type Vulnerabilities: Both diseases affect upper and lower motor neurons and specific cortical neurons, such as Betz cells in ALS and von Economo neurons in FTLD, suggesting overlapping mechanisms of neurodegeneration.
  • Molecular Insights: Single-nucleus RNA sequencing revealed conservation of gene dysregulation across cell types in ALS and FTLD, indicating a shared molecular basis. The study identified potential therapeutic targets and established a transcriptional link between vulnerable cell populations across the nervous system in ALS and FTLD.

References:

  1. Abramzon YA, Fratta P, Traynor BJ, Chia R. The Overlapping Genetics of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Frontiers in neuroscience. 2020;14. doi:10.3389/FNINS.2020.00042
  2. Brettschneider J, Del Tredici K, Toledo JB, et al. Stages of pTDP-43 pathology in amyotrophic lateral sclerosis. Annals of neurology. 2013;74(1):20-38. doi:10.1002/ANA.23937
  3. Pineda SS, Lee H, Ulloa-Navas MJ, et al. Single-cell dissection of the human motor and prefrontal cortices in ALS and FTLD. Cell. March 2024. doi:10.1016/J.CELL.2024.02.031

Affiliations:

1Neurology Unit, IRCSS Policlinico San Donato, San Donato Milanese, Italy

2Vita-Salute San Raffaele University, Milan, Italy

Publish on behalf of the Scientific Panel ALS and frontotemporal dementia

Back