Abstract
Axonal degeneration is a common endpoint in peripheral neuropathies. In Charcot‐Marie‐Tooth (CMT)
disease, a subgroup of patients presents with primary axonopathies (CMT2), but secondary axonal
degeneration occurs in all demyelinating forms of CMT (CMT1) as well. Mutations in the MPZ gene
encoding myelin protein zero (P0), the main peripheral myelin protein, typically lead to a severe, earlyonset
demyelinating neuropathy (CMT1B). Notably, the T124M mutation in P0 causes an axonopathy,
referred to as CMT2J, with late onset and only minimal myelin defects. The mechanism by which this
mutation in a myelin protein causes an axonal neuropathy remains unclear. This Joint PhD project aims
to unravel the mechanisms of axonal degeneration in CMT2J and to evaluate potential therapeutic
interventions with the use of in vivo and novel in vitro models.
The group of Dr. Maurizio D'Antonio has generated a mouse model carrying the P0‐T124M mutation,
which presents clinical characteristics consistent with those observed in patients and has used this
mouse model to follow disease progression and test different genetic knock‐out strategies. Recent
data revealed dysregulated pathways that may underlie axonal degeneration, like abnormalities in
axon‐glial exchange areas, defects in mitochondria and possible in axonal transport. The latter was
confirmed through in vivo imaging of retrograde endosome transport. Endosomes in homozygous
T124M mice move slower and pause more frequently than in wild type control mice. A potential
strategy to rescue this phenotype is the deletion of HDAC6, the main deacetylase of α‐tubulin, as
microtubule integrity is crucial in axonal transport. Notably, HDAC6 inhibitors are commercially
available and are concurrently being tested in mouse models for other neurogenerative diseases and
even in clinical trials for cancer research. As CMT2J is a late‐onset disease, animal studies and therapy
development are extremely extensive and time‐consuming and unfortunately, there are currently no
suitable cellular models available.
To bridge this gap, the Timmerman lab will generate advanced iPSC‐derived neuromuscular
assembloids (NMAs) and/or organoids (NMOs) for CMT2J. These in vitro models closely mimic the
human peripheral nervous system and offer a unique platform for detailed studies of cellular
interactions. They will provide additional means to study the molecular mechanisms behind the
mutant P0‐T124M induced axonopathy, as well as to test HDAC6 inhibition as a therapeutic strategy.
By merging advanced genetic tools with innovative cell culture techniques, this PhD project seeks not
only to provide insights into the pathophysiology of CMT2J but also to contribute broadly to
neurodegenerative disease research and therapy development.
Researcher(s)
Research team(s)
Project type(s)