Gerardo A. MORFINI

Associate Professor, Department of Anatomy and Cell Biology University of Illinois at Chicago, USA

Tuesday 11 May 2021 |2:00 pm – ICGEB Trieste, ITALY

A unique marine organism reveals a novel pathogenic mechanism in Huntington’s disease and a novel potential therapeutic target

Host: F. Feiguin

Huntington’s disease (HD) is a devastating neurological disorder caused by mutations in the gene encoding huntingtin, a protein of unknown function. Cumulative evidence established axonal degeneration as an early pathogenic event contributing to the gradual loss of corticostriatal connectivity that characterizes HD. However, mechanisms and specific molecular components linking mutant huntingtin to axonal pathology remain unknown. An understanding of such mechanisms might inspire the development of novel therapeutic treatments aimed to preserve neuronal connectivity in HD.

In this seminar, I will first summarize findings from experiments in the squid axoplasm preparation, a unique experimental system for the isolated study of molecular events in the axonal compartment. Collectively, these findings revealed a mechanism where mutant huntingtin promotes aberrant activation of the protein kinase JNK3 and inhibition of axonal transport, a major cellular process sustaining synaptic function and axonal health. Following this introduction, I will present recent work evaluating the relevance of these findings to mammalian neurons, which involved genetic deletion of JNK3 in a well-established HD mouse model. Finally, I will present data suggesting a novel mechanist basis linking mutations in huntingtin to abnormal activation of a kinase pathway upstream of JNK3.