Motor axon development in a zebrafish model of Charcot-Marie-Tooth disease

Williams College, Williamstown MA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Charcot-Marie-Tooth disease (CMT), the most common inherited neuromuscular disorder, is a progressive disease characterized by degeneration of long motor and sensory axons, resulting in muscle atrophy and long-term disability. Distal hereditary motor neuropathy (dHMN) is a very closely-related disease characterized by motor, but not sensory, axon degeneration. These diseases usually show dominant inheritance, with symptoms first appearing during the second or third decade of life. Mutations in any one of several genes are known to cause either or both diseases. For example, mutations in the small heat shock proteins (sHSPs) HSP27 or HSPB8 can cause either CMT or dHMN. sHSPs are well known for their roles in protecting cells from the effects of environmental stressors and for regulating actin and intermediate filament dynamics. Misexpressing the disease-causing variants of HSP27 in cultured cells results in aggregation of intermediate filament proteins, suggesting that the axonal degeneration characteristic of CMT and dHMN may be due to either the sequestration of intermediate filaments and subsequent failure to appropriately establish or maintain axon architecture, or toxicity of protein aggregates. Understanding the etiology of these diseases is complicated by the large degree of heterogeneity within families -- and between at least two identical twins -- suggesting that environmental and/or multiple genetic factors may contribute to disease progression. Finally, while the mutations are assumed to act autonomously within neurons, HSP27 is expressed in developing muscle and it is upregulated in adult muscle in response to physiologic stress. Using zebrafish as a model system, we propose to determine (1) how HSP27 disease mutations affect the development and maintenance of motor axons, (2) whether the mutations sensitize axons to the effects of environmental stress, and (3) whether HSP27 is required in neurons, muscle, or both. In order to accomplish these objectives, we will misexpress zebrafish versions of the HSP27 disease variants (all of which act dominantly) in the zebrafish, either ubiquitously or in neurons or muscle and assay the effects on the development and maintenance of motor axon architecture and protein aggregation. The results of these studies will help us to better understand the cell biological events leading to axon degeneration in CMT and dHMN. Furthermore, since the progression and severity of CMT and dHMN are likely determined, at least in part, by environmental factors, the results of these studies could have direct implications for the prevention and management of these diseases. PUBLIC HEALTH RELEVANCE This research outlined in this proposal is designed to address how mutations in the small heat shock protein Hsp27 cause two neurodegenerative diseases, Charcot-Marie-Tooth Disease and Distal Hereditary Motor Neuropathy and to test whether environmental stress contributes to their development or progression. The results of these studies could significantly impact our ability to prevent or slow progression of the diseases, thus improving the quality of life of these patients as well as reducing health care costs associated with treating their symptoms. [unreadable] [unreadable]