CMT 2E and 2F: Disruption of neurofilament network with aggregation of light neu

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Disruption of neurofilament network with aggregation of light

neurofilament protein: A common pathway leading to motor neuron

degeneration due to Charcot-Marie-Tooth disease-linked mutations in

NFL and HSPB1

Jinbin Zhai1,*, Hong Lin1, Jean-Pierre n2 and W.

Schlaepfer1

1 Division of Neuropathology, Department of Pathology and Laboratory

Medicine, University of Pennsylvania School of Medicine,

Philadelphia, PA 19104, USA 2 Department of Anatomy and Physiology,

Laval University Research Centre, Centre Hospitalier de l'Université

Laval, Québec QC G1V 4G2, Canada

* Corresponding author: Jinbin Zhai, Ph.D. Division of

Neuropathology Department of Pathology & Laboratory Medicine

University of Pennsylvania School of Medicine 606C Stellar-Chance

Laboratories 422 Curie Boulevard Philadelphia, PA 19104 - 6100 :

Mutations in neurofilament (NF) light subunit (NFL) and small heat-

shock protein B1 (HSPB1) cause autosomal-dominant axonal Charcot-

Marie-Tooth disease type 2E (CMT2E) and type 2F (CMT2F). Previous

studies have shown that CMT mutations in NFL and HSPB1 disrupt NF

assembly and cause aggregation of NFL protein. In this study, we

investigate the role of aggregation of NFL protein in the

neurotoxicity of CMT mutant NFL and CMT mutant HSPB1 in motor

neurons. We find that expression of CMT mutant NFL leads to

progressive degeneration and loss of neuronal viability of cultured

motor neurons. Degenerating motor neurons show fragmentation and

loss of neuritic processes associated with disruption of NF network

and aggregation of NFL protein. Co-expression of wild-type HSPB1

diminishes aggregation of CMT mutant NFL, induces reversal of CMT

mutant NFL aggregates and reduces CMT mutant NFL-induced loss of

motor neuron viability. Like CMT mutant NFL, expression of S135F CMT

mutant HSPB1 also leads to progressive degeneration of motor neurons

with disruption of NF network and aggregation of NFL protein.

Further studies show that wild-type and S135F mutant HSPB1 associate

with wild-type and CMT mutant NFL and that S135F mutant HSPB1 has

dominant effect on disruption of NF assembly and aggregation of NFL

protein.

Finally, we show that deletion of NFL markedly reduces degeneration

and loss of motor neuron viability induced by S135F mutant HSPB1.

Together our data support the view that disruption of NF network

with aggregation of NFL is a common triggering event of motor neuron

degeneration in CMT2E and CMT2F disease.