Hypermetabolism as a Risk Factor for ALS
Abstract
ALS, a fatal adult-onset disease, is a neurodegenerative disorder that affects motor neurons in the brain and the spinal cord. What causes ALS remains incompletely understood and no disease modifying therapy is currently available. Recent discovery of an ALS gene called Tat Activating Regulatory DNA Binding Protein (TDP-43) encoding a protein involved in RNA metabolism, provided opportunities to clarify disease pathogenesis and hold promise for development of new therapies. Our recent discovery in mice that lack Tdp-43 showed that these mice excessively burned out their body fat, likely working through a protein called Tbc1d1 which is known to control fat metabolism in skeletal muscle. To test this hypothesis, we generated conditional Tdp-43 knockout mice using a muscle-specific (MLC) driver of Cre recombinase. Loss of Tdp-43 in skeletal muscle led to adult onset weight loss beginning about 3 months of age followed by premature death within a month. Pathological examination of skeletal muscles revealed degeneration of fibers as well as marked regeneration, observations that are consistent with a myopathy occurring in these mice. These new findings suggest an important role for Tdp-43 in skeletal muscle that may contribute to the pathogenesis of ALS and possibly a select group of myopathies.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2012
- Accession Number
- ADA567777
Entities
People
- Philip C. Wong
Organizations
- Johns Hopkins University