Another important step forward in the identification of the genes responsible for ALS with the decisive contribution of Italian scientists. The effort to identify genes responsible for amyotrophic lateral sclerosis (ALS) takes a significant step forward thanks to the international collaboration that achieves a significant result published in the journal Nature Genetics. In this “genome-wide” or GWA association study, which allows the simultaneous analysis of all the genes of an individual, the DNA of 29,612 patients with sporadic ALS and 122,656 healthy subjects were analyzed, with the identification of 15 variants genes associated with the disease. These variants affect genes involved in specific metabolic pathways and related to neurodegenerative processes also of other diseases such as vesicular transport mechanisms between the Golgi apparatus and the endoplasmic reticulum, autophagy with evidence of primary involvement of glutamatergic motor neuron cells.
I study
The study is the result of an extensive international collaboration led by Prof. Jan Veldink of the University of Utrecht, in the Netherlands, which was attended by institutions from all over the world. Among the Italian research groups, the Neuroscience Laboratory and Neurology Unit of the Italian Auxological Institute IRCCS which supported the research together with the University of Milan and the “Centro Dino Ferrari”. The group includes Dr. Isabella Fogh and professors Nicola Ticozzi and Antonia Ratti of the University of Milan, coordinated by prof. Vincenzo Silani.
“The recent study – explains prof. Vincenzo Silani, Full Professor of Neurology at the University of Milan, head of neurology at Auxologico San Luca in Milan and founder of the Italian Consortium SLAGEN – confirmed, among the 15 loci associated with the disease, 8 genes already identified in previous studies ( UNC13A, SCFD1, MOBP / RPSA, KIF5A, CFAP410, GPX3 / TNIP1, NEK1 and TBK1) further proving the respective pathogenetic involvement. D.However, the identification of 7 new loci that contribute to better delineate the specific neurodegeneration mechanisms of the disease is of particular importance. The study showsin fact, the expression of genes involved in particular in glutamatergic motor neurons, thus suggesting that the neurodegenerative process in ALS is originally borne by the neuronal cell and not microglial or astrocytic. In particular, the role of both vesicle transport and autophagy is demonstrated as a determinant of neuronal loss with particular involvement of the Golgi complex and the endoplasmic reticulum. Lastly, high cholesterol levels seem to play a causal role for ALS as will be further underlined by an outgoing work by the same group ”.
The relationship with other neurodegenerative diseases
Very interesting is the sharing of pathogenetic genes reported with other neurodegenerative diseases such as Alzheimer’s, Parkinson’s, corticobasal degeneration, progressive supranuclear palsy and frontotemporal dementia further validating the assumption of common pathogenetic mechanisms for the various neurodegenerative diseases.
“This powerful study by GWA – concludes prof. Vincenzo Silani – differs from the previous ones due to the large number of patients analyzed and the completeness of information reached with the inclusion of ALS alongside other neurodegenerative diseases because it shares common pathogenetic mechanisms with the indication of a primitive neuronal process at the origin of the disease, thus reinforcing the concept of a selective vulnerability of the motor neuron cell in ALS “.
The effort of the group of prof. Silani, started in 2014 with a first study by GWA on a large series of ALS patients, is now strengthened with this new large-scale work aimed at identifying genes and pathogenetic mechanisms of ALS, in a context increasingly shared with other neurodegenerative diseases. The prospect of being able to act on shared mechanisms between different pathologies constitutes the prerequisite for a therapeutic alliance aimed at rapidly defining effective therapeutic approaches, it being understood that the target remains the spinal motor neuron responsible for the biological graft of the disease.