1. Pathophysiology of Kidins220-linked human neurodevelopmental disorders

The research of my group is focused on understanding the pathogenic mechanisms underlying rare neurodevelopmental disorders linked to mutations in the KIDINS220 gene.

Kinase D-interacting substrate of 220 kDa, also known as Ankyrin repeat-reach membrane spanning (Kidins220/ARMS)(Scholz-Starke and Cesca, Front Cell Neurosci 2016) is a transmembrane scaffolding protein whose expression is enriched in the nervous system. Previous studies in vitro and in vivo have highlighted the role of Kidins220 as a mediator of NGF and BDNF intracellular signaling pathways during neuronal development and differentiation and in synaptic plasticity. The complete ablation of Kidins220 in mice leads to embryonic lethality with widespread apoptosis in the central and peripheral nervous system and cardiovascular defects (Cesca et al, Cell Death Dis 2011; Cesca et al, Cell Death Diff 2012).

Recently, three patients were diagnosed with Spastic paraplegia, Intellectual disability, Nystagmus and Obesity (SINO) caused by heterozygous mutations in KIDINS220 (Josifova et al, Hum Mol Genet 2016). KIDINS220 variants also lead to spastic paraplegia and obesity (Yang et al, Eur J Neurol 2018) or spastic paraplegia only (Zhao et al, Mol Diagn Ther 2019). Remarkably, KIDINS220 mutations are not compatible with life when in homozygosis (Mero, Hum Mol Genet 2017).

Several Kidins220 isoforms exist (Schmieg et al, PLoS One 2015) and interestingly, some pathogenic mutations would generate proteins similar to the shortest physiological isoforms. We hypothesize that SINO can be explained by alterations of the physiological Kidins220 isoform expression pattern, combining (i) loss-of-function phenotypes, since the expression of the full length and most common isoform is reduced, and (ii) gain-of-function phenotypes, since shorter forms are aberrantly expressed.

Nothing is yet known about the mechanisms by which KIDINS220 mutations cause spastic paraplegia and associated symptoms, and patients currently face a complete lack of knowledge about their pathology. By combining in vitro and in vivo studies on animal models as well as on engineered stem cells and patient-derived samples, we aim at addressing this important mechanistic gap in knowledge.

Schematic representation of the structure and domain composition of Kidins220. The pathogenic mutations identified to date are indicated, as follows:

[1] El-Dessouky et al, Am J Med Genet 2020 (red)
[2] Lam et al, Clin Dysmorphol 2020 (magenta)
[3] Mero et al, Hum Mol Genet 2017 (green)
[4] Josifova et al, Hum Mol Genet 2016 (blue)
[5] Yang et al, Eur J Neurol 2018 (orange)
[6] Zhao et al, Mol Diagn Ther 2019 (purple)

Main collaborators

Dr. F. Benfenati, IIT Center for Synaptic Neuroscience and Technology (IIT-NSYN), Genova, Italy
Dr. G. Schiavo, Institute of Neurology, University College of London, UK
Dr. T. Iglesias, Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM), Madrid, Spain

2. Physiology and pathophysiology of astrocytes.

In recent years, glial biology has witnessed a sort of ‘scientific renaissance’. Initially considered just passive bystanders providing structural support to neurons, astrocytes are now known to participate in all fundamental processes of neuronal physiology, including development, synaptic plasticity, and higher cognitive functions. At the same time, astrocytes have been identified as active players in pathologies traditionally considered purely, or mainly, neuronal, including autism spectrum disorders (ASD) and genetic diseases such as the fragile X and Rett syndromes. This offers exciting opportunities in biomedical research, as it may lead to the development of novel therapeutic strategies targeting astroglial alterations in neuropathologies (Santello et al, Nat Neurosci 2019).

The aim of this project is two-fold:

• to get more insights into the physiology of primary astrocytes. More in detail, we characterize the response of astrocytes to a variety of trophic factors, including BDNF, in terms of intracellular signaling, Ca²⁺ dynamics and gliosecretion;
• to unravel the contribution of astroglia to selected neuropathologies.

Confocal microscopy image of a primary mouse astrocyte in culture, labelled with glial fibrillary acidic protein (GFAP) in green, and with DAPI to visualize the nucleus (in blue). Scale bar, 10 µm.

Main collaborators

Prof. S. Ferroni, University of Bologna, Italy