Autophagy dysregulation in cerebral palsy: a common mechanism.

Cerebral palsy (CP) is a clinical descriptive term that defines a heterogeneous group of non- progressive, neurodevelopmental disorders of motor impairment, which co-occur with a wide range of medical conditions, such as intellectual disability (ID), speech and language deficits, autism, epilepsy and visual and/or hearing impairment. It is the most frequent cause of motor impairment in children, with an important impact on quality of life and a prevalence ranging from 1.5 to 2.5 in 1000 live births. The causes of CP are quite variable. Recent studies demonstrate an important contribution of genetic causes. However, a common mechanism of action of the genes associated with CP is largely unknown. This prompted us to perform genetic analysis in our CP-patient cohort using Single Nucleotide Polymorphism (SNP) array and Whole Exome Sequencing (WES). In this project, we investigate the hypothesis that a subset of genetic causes of CP affect ATG9A transport and subsequently lead to a dysregulation of autophagy. Autophagy is a self-degradative cellular process that removes redundant/dysfunctional proteins, organelles or pathogens. Autophagy was already demonstrated to be an important neuroprotective mechanism against hypoxia-ischemia and glutamate excitotoxicity in animal models. This hypothesis is based on: 1. The important contribution of pathogenic de novo missense variants in KIF1A in our CP cohort (identified in 7/ 141 CP cases). KIF1A is a member of the kinesin motor protein family and is responsible for cargo transport along microtubular tracts. A major cargo of KIF1A is ATG9A, a key regulator of autophagy induction at the presynaptic synapses. 2. In the AP-4 deficiency syndrome, the first known genetic cause of CP, mislocalisation of ATG9A was already demonstrated to be the causal mechanism for the CP phenotype. 3. The identification of likely pathogenic variants in known CP genes (KIF5C) and interesting novel CP candidate genes (KLC3, KLC4, MAP7D2, MAP7D3) that may affect ATG9A transport. In the project, we will study the effect of 1) KIF1A variants and of 2) variants in other CP (candidate) genes on ATG9A and the autophagy process in patients' and controls' fibroblasts. Furthermore, we perform RNA-sequencing in blood and fibroblasts to determine a common expression profile leading to an "autophagy dysregulation" signature. This signature could have important future clinical relevance in screening for potential autophagy dysregulation and monitoring future treatment strategies targeting autophagy.

Keywords:NEUROGENETICS, NEUROLOGY, PEDIATRICS

Disciplines:Developmental genetics, Genetic predisposition, Genetics not elsewhere classified, Developmental neuroscience, Paediatrics