Riassunto analitico
Amyotrophic lateral sclerosis is a progressive neurodegenerative disease characterized by progressive muscle weakness leading to disability and eventually death in a few years. Despite its aggressive clinical course, a huge heterogeneity in clinical manifestations and survival does exist among patients, with fast and slow disease progression that remains to be elucidated.
Several mechanisms are involved in disease pathogenesis, emerging themes include impairment in RNA metabolism, disfunctions in protein quality control (PQC) systems, that also represent a target for experimental treatments, and impairment of functionality and dynamics ribonucleoprotein (RNP) granules, such as Stress Granules (SGs).
For this thesis we studied clinical and biological features of 54 patients enrolled in the no-profit clinical trial co-ALS. In this clinical trial patients with sporadic ALS with bulbar or classic presentation and with an onset not longer than 18 months, where treated with colchicine or placebo. The clinical trial is still going on and it is still double blinded; nevertheless, patients’ follow up from enrolment is still going on.
We studied several clinical and biological variables measured in these patients at baseline and at week 30. Among these, we focused on disease progression, on cerebrospinal fluid (CSF) and serum biomarkers, and on SGs response and DRiPs enrichment in fibroblasts obtained from patients’ skin biopsies at baseline and at week 30.
There were 18 women and 36 men in the study, with a mean age at onset of 57,16. During the study 5 patients died, and 15 underwent nutritional or respiratory supporting measures.
Among these subjects mean disease progression rate measured at baseline by monthly decline of the ALSFRS-R total score was 0.73 points/month, in agreement with literature data. From baseline to week 30 there was a slowing down of disease progression in 7 patients, whereas 17 patients continued to progress as expected.
These two patients’ groups differed because of defective ribosomal products (DRiPs) enrichment in SGs. Patients who presented a decrease in disease progression speed had a significantly lower frequency of SGs highly enriched with DRiPs in comparison with patients who did not experience a decrease in disease progression. With the limit of a very small number of patients we also found that survival was influenced by levels of CSF pNfH and respiratory function assessed by FVC at baseline.
For the first time disease progression rate appears to be correlated with DRiPs’ enrichment in SGs of fibroblasts from ALS patients, opening an interesting new window on possible biomarkers of protein quality control system activity regulating disease progression.
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