Genetics and cell biology
Biology of myelin
Myelin is a specialized structure that surrounds large axons and permits rapid conduction of nerve signals. It is formed by oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system. During development, these cells migrate with the axons that they will myelinate, and depend on those same axons for appropriate signals to survive and differentiate. Myelin-forming glia coordinately express a unique set of genes encoding myelin structural proteins, and enzymes that synthesize myelin lipids-this coordination is in large part transcriptionally-mediated. Mutations in these proteins, including peripheral myelin specific proteins such as myelin protein zero (P0/MPZ) and peripheral myelin protein 22 (PMP22), are associated in humans to hereditary neuropathies, collectively known as Charcot-Marie-Tooth (CMT) disease.
Research activity
This unit is devoted to study the molecular mechanisms underlying these diseases, with the goal of identifying effective therapeutic strategies. To this aim we have developed/acquired a cohort of mice carrying mutations in MPZ or PMP22 and systematically dissected the disease mechanism.For example, in a group of mutations in MPZ, causing CMT type 1B, we have identified protein misfolding and activation of stress pathways such as the unfolded protein response (UPR) as crucial pathomechanisms. Importantly, these mechanisms are shared by the duplication of PMP22 (causing CMT1A, the most common form of CMT) and by missense mutation in PMP22 (causing CMT1E). One of the main areas of research in the lab is the genetic and pharmacological modulation of the UPR as a potential therapeutic target.
At the same time, in most forms of CMT, axonal loss plays a key role in disease progression. A second area of research in the unit is devoted to the identification and correction of pathways that lead to axonal degeneration.
Finally, the laboratory has recently started a new line of research aimed at exploring gene editing strategies as a therapeutic avenue of autosomal dominant forms of CMT1.
