Periodic Reporting for period 3 - Neurovulnerability (Molecular mechanisms underlying selective neuronal death in motor neuron diseases)
Periodo di rendicontazione: 2022-08-01 al 2024-01-31
Spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) are progressive motor neuron diseases for which there is no cure. Although both SMA and ALS are considered rare diseases based on their prevalence, their socioeconomic impact is extensive. The average annual cost per ALS patient is over 70.000€ in European countries, and an increase in incidence of around 69% is predicted till 2040 due to ageing of the population. SMA, with an incidence of ~1 in 6,000 live births and a carrier frequency of ~1/50, raises an annual average cost of over 40.000€ per patient plus ~300.000€ per year and patient for two of the three recently FDA-approved drugs and ~1 million euro per patient for the recently approved gene therapy. This is a huge socio-economic impact, besides the obvious devastating effect on patients, their families and their care-givers.
Despite decades of intense investigation there are still no curative treatments and the main reason is that we still ignore the mechanisms behind the selective neuronal death that characterizes these neurodegenerative diseases. In our team we are convinced that all these years, research has addressed the problem of motor neuron death in a wrong way, assuming that all motor neurons are similarly affected and should therefore be treated in the same manner. Now we know that a given neuropathology, including SMA and ALS, does not impact all neurons of the same type to a similar level; however, we still ignore why. We believe that the answer to that question holds the key for truly understanding the nature of these diseases. Using a variety of approaches ranging from cellular biology techniques and live imaging to genome editing and single cell omics, and utilizing human induced pluripotent stem cells together with transgenic animal models, our team investigates the molecular mechanisms underlying such fascinating selective motor neuron death. We devote a special focus at exploring the molecular basis of proteostasis failure, major causative event in neurodegeneration. Our ultimate goal is to understand the molecular origin of this distinctive neuronal vulnerability to design effective therapeutics targeting specific neuronal subtypes or phases of the disease.
Despite decades of intense investigation there are still no curative treatments and the main reason is that we still ignore the mechanisms behind the selective neuronal death that characterizes these neurodegenerative diseases. In our team we are convinced that all these years, research has addressed the problem of motor neuron death in a wrong way, assuming that all motor neurons are similarly affected and should therefore be treated in the same manner. Now we know that a given neuropathology, including SMA and ALS, does not impact all neurons of the same type to a similar level; however, we still ignore why. We believe that the answer to that question holds the key for truly understanding the nature of these diseases. Using a variety of approaches ranging from cellular biology techniques and live imaging to genome editing and single cell omics, and utilizing human induced pluripotent stem cells together with transgenic animal models, our team investigates the molecular mechanisms underlying such fascinating selective motor neuron death. We devote a special focus at exploring the molecular basis of proteostasis failure, major causative event in neurodegeneration. Our ultimate goal is to understand the molecular origin of this distinctive neuronal vulnerability to design effective therapeutics targeting specific neuronal subtypes or phases of the disease.
Our work has allowed us to endogenously label, for the first time, the most critical protein for the survival of all spinal motor neurons, SMN, with a fluorescent reporter, which enables us to track individual human motor neurons in culture, study how the regulation of this protein’s levels determines the development of these neurons and their integration into a neural circuit, and ultimately, unravel why and how they degenerate in a specific manner in SMA and ALS. This study has also empowered us to discover a new function of SMN protein on lysosomal biology. These findings may change our current understandings of SMA and ALS and thus provide a base for combinatorial treatments, anticipated to be needed for efficacious future therapies.
Through this study, our ultimate goal is to unravel the molecular and cellular basis of the selective neuronal death occurring in the motor neuron diseases SMA and specific familial forms of ALS. Specifically, we expect to understand how the heterogeneity of SMN protein levels among individual motor neurons is regulated, how this heterogeneity determines the fate of each motor neuron, how this essential protein controls general protein homeostasis and whether unknown SMA disease modifiers can be discovered and could help the development of new and better motor neuron disease therapies.