Investigating the Role of OCRL, the Gene Mutated In Lowe Syndrome, in Neurons

Morra, Valentina (2020). Investigating the Role of OCRL, the Gene Mutated In Lowe Syndrome, in Neurons. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0001138e

Abstract

Lowe syndrome, also known as Oculo-Cerebro-Renal syndrome of Lowe, is a rare X-linked condition that primarily affects the eye, the nervous system and the kidney.

OCRL, the gene mutated in Lowe syndrome, encodes an homonymous protein called OCRL which is an inositol polyphosphate 5-phosphatase acting preferentially on PtdIns(4,5)P2. OCRL is known to exert several relevant functions in both non-neuronal and neuronal cells. In neurons, PtdIns(4,5)P2, by binding its effectors, acts as an important regulator of processes indispensable for synaptic transmission such as exocytosis, endocytosis and recycling of synaptic vesicles. Whereas the roles of OCRL in non-neuronal cells have been widely explored over the last years, studies focused on its roles in neuronal cells are still missing. Hence, the pivotal role of PtdIns(4,5)P2 in neurons together with the main neurological features of Lowe syndrome (intellectual disability and epilepsy) prompted us to investigate the role of OCRL in the brain. Here I show that in the absence of OCRL neurons exhibit impaired recycling of synaptic vesicles accompanied by an imbalance between excitatory and inhibitory functions in OCRL-depleted hippocampi. Moreover, under neuronal stimulation an increase in the levels of PtdIns(4,5)P2 at OCRL-depleted synapses is observed. These defects, which can be attributed to dysfunctional PtdIns(4,5)P2 metabolism due to the absence of OCRL, result in an increased number and size of endocytic structures with a decrease in the number of synaptic vesicles available for neuronal functions.

These findings shed light on the role of OCRL in neurons, which, by co-operating with other lipid phosphatases such as synaptojanin 1, ensures a correct balance between PtdIns(4,5)P2 synthesis and degradation at synapses, thus controlling crucial mechanisms in neurotransmission.