Lectures and seminars CMB Seminar - Antony Cougnoux

"Analysis of Niemann-Pick type C1 mice cerebella and evaluation of therapeutic targets"

Niemann-Pick Type C1 (NPC1) disease is characterized by the autonomous death of cerebellar neurons and neuroinflammation. Here we studied the involvement of a protein at the crossroad between cell death and inflammation: the receptor interacting protein kinase 1 (RIPK1). This protein regulates two types of cell death: apoptosis and necroptosis.

The lack of involvement of apoptosis in the disease was known, therefore, we focused on necroptosis signaling in NPC1 cerebella and cell culture models. We demonstrated that NPC1 patient skin fibroblasts spontaneously died in culture through necroptosis, in a disease severity-dependent manner. The addition of RIPK1 inhibitors, necrostatins (Nec-1 and 1s), or its silencing by siRNA significantly reduced the spontaneous cell death, unlike addition of caspase or RIPK3 inhibitors. Treating Npc1 mice with RIPK1 inhibitors delayed the onset of neurological symptoms, the loss of the Purkinje neurons characteristic for NPC1 disease in a dose dependent manner and extended the lifespan by 15-20%. RIPK1 inhibition in combination with NPC1 reference treatment: 2-hydroxypropyl-beta-cyclodextrin (HPβCD) showed an additive effect increasing the lifespan of the animals.