HDAC4 and Amyotrophic Lateral Sclerosis

ALS is a neurodegenerative disease characterized by progressive loss of upper and lower motor neurons (Robbins et al. 2010). With an incidence of 2 per 100,000 per year, this is a rare but devastating disease. Symptom onset is usually in the fifth decade, beginning with decreased fine motor control and coordination. Typically, motor strength and function continues to decline over a 3- to 5-year time course until patients succumb to death due to inability to breathe or swallow. Only 10% of the cases are familial (fALS) with the remaining 90% being sporadic. Of the fALS cases, roughly 20% are associated with a gain-of-function mutation in the superoxide dismutase-1 (SOD-1) gene. Although a number of mutations have been associated with ALS, the underlying pathogenesis remains elusive. Signs and symptoms of ALS result directly from the death of motor neurons, leading to a gradual loss of neural input into myofibers and subsequent neurogenic muscle atrophy. Currently, the only effective treatment for ALS is riluzole, which extends the life span of ALS patients by only a few months (Doble 1996). As the primary pathogenesis is unknown, therapeutic strategies targeting the underlying cause of ALS are limited. Thus, therapy must focus on the

Fig. 3 (a) Deltoid muscle biopsies taken from patients at the Duke ALS clinic were homogenized and analyzed for HDAC4 and actin levels by immunoblotting. Healthy control: 1, 6, 9; myopathy patients: 2, 4, 7; ALS patients: 5,10. (b) Muscle biopsy from healthy control 1, and ALS patient 5 were sectioned and processed for immunofluorescence microscopy using HDAC4 (red) and dystrophin antibodies (DYS). Hoechst dye was used to identify nuclei. Arrowheads in merged images indicate the accumulation of HDAC4 within nuclei of highly atrophic muscle

Fig. 3 (a) Deltoid muscle biopsies taken from patients at the Duke ALS clinic were homogenized and analyzed for HDAC4 and actin levels by immunoblotting. Healthy control: 1, 6, 9; myopathy patients: 2, 4, 7; ALS patients: 5,10. (b) Muscle biopsy from healthy control 1, and ALS patient 5 were sectioned and processed for immunofluorescence microscopy using HDAC4 (red) and dystrophin antibodies (DYS). Hoechst dye was used to identify nuclei. Arrowheads in merged images indicate the accumulation of HDAC4 within nuclei of highly atrophic muscle manifestations of ALS, namely the association of the motor neuron and myofiber as well as neurogenic muscle atrophy.

HDAC4 is a critical regulator of neurogenic muscle atrophy (Moresi et al. 2010), a dominant manifestation of ALS. In human ALS patients, HDAC4 is dramatically induced (Fig. 3a) and accumulates in the nuclei of skeletal muscle (Fig. 3b). A similar deregulation of HDAC4 is observed in an ALS mouse model caused by a human SOD-G93A transgene (Cohen et al. 2007). These observations suggest that HDAC4 might be a potential therapeutic target for ALS and related motor neuron diseases. Given the prominent role of HDAC4 in neurogenic muscle atrophy and synapse regulation, it would be of great clinical importance to investigate whether inhibition of HDAC4 could stimulate the reinnervation of NMJ and suppress muscle atrophy in ALS patients.

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