Disruption of neurofilament network with aggregation of light neurofilament prot

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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, School of Medicine, University of Pennsylvania,

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

Division of Neuropathology, Department of Pathology and Laboratory

Medicine, School of Medicine, University of Pennsylvania, 606C

Stellar-Chance Laboratories, 422 Curie Boulevard, Philadelphia, PA

19104-6100, USA. Tel: +1-215-662-6696; Fax: +1-215-573-2059

Mutations in neurofilament light (NFL) subunit 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.