28 Ottobre 2019, ore 14.00
Sebastian Lewandowski (Royal Institute of Technology, KTH, SciLifeLab Karolinska Institutet Stockholm, Sweden)
"The vascular brain, how perivascular fibroblasts contribute to sporadic ALS neurodegeneration"
For decades, ALS has been defined (and diagnosed) based on symptoms of rapid, age-dependent degeneration of motor neurons. Recent evidence, however, suggests that this symptomology often fails to include complex input from other cell types that are critical to disease progression. Apart from genetic mechanisms intrinsic for neurons, few reports show that the variability of sporadic ALS progression and onset also depends on complex contributions from many other cell functions that include glial response and blood vessel integrity. Still, most of the attention is too often focused on the defined, neuron-centric, post-onset mechanisms and unless we understand how non-neuronal cells such as blood vessels contribute to ALS aetiology, early diagnosis, clinical trial design and effective treatments will likely remain elusive.
Here it is presented transcriptional activity patterns for ten nervous system cell types in human and murine ALS to show that perivascular fibroblasts become active before symptom onset and remodel blood vessels with specific proteins that consistently predict short patient survival. (1) It is inferred RNA transcript enrichments for ten cell types using single-cell and bulk tissue transcriptomes and demonstrate that sporadic ALS patients and mouse model spinal cords represent coherent cell activity patterns and that contributions from vascular cells largely precede input from microglia or astrocytes. (2) Notably, perivascular fibroblasts elicit the strongest pre-onset enrichments and their specific proteins SPP1 and COL6A1 accumulate in remodelled perivascular spaces in sporadic ALS patients. (3) Moreover, the increase of SPP1 and COL6A1 in blood plasma at disease diagnosis repeatedly predict shorter survival in 688 ALS patients from three country cohorts.
It is proposed that pre-onset cellular mechanisms of ALS are more complex than originally thought and that perivascular fibroblast cells contribute earlier and to a greater extent than previously appreciated to sporadic ALS disease survival. Since vascular space remodelling consistently occurs in ageing and numerous forms of neurodegeneration, the perivascular fibroblast activity can represent a common mechanism that could help to redefine the cerebral injury response and become a novel aim for targeted therapies.
Ed. Fisiologia Umana e Biochimina CU027