The purpose of this research program is to investigate the mechanisms of hereditary neurological diseases, with the ultimate intent of developing effective treatments for these disorders. Recently, the research has focused on two specific neuromuscular diseases: autosomal recessive spinal muscular atrophy (SMA) due to deficiency of the protein SMN, X-linked spinal and bulbar muscular atrophy (SBMA) due to polyglutamine expansion in the androgen receptor. Specific research accomplishments reported recently include the following: (1) Identification of an E3 ligase, mind bomb 1 (Mib1), responsible for the degradation of SMN protein. SMN is ubiquitinated and degraded through the ubiquitin proteasome system (UPS). We have previously shown that proteasome inhibition improves motor function, and reduces spinal cord, muscle, and neuromuscular junction pathology of spinal muscular atrophy mice, suggesting that the UPS is a potential therapeutic target for this disease. While inhibiting the proteasome provides proof of concept that the UPS can be targeted to increase SMN protein levels, specific targets in this pathway may be more efficacious and less toxic. In this study, we show that the E3 ubiquitin ligase, Mib1, interacts with and ubiquitinates SMN and facilitates its degradation. Knocking down Mib1 levels increases SMN protein levels in cultured cells. In addition, knocking down the Mib1 ortholog improves neuromuscular function in Caenorhabditis elegans deficient in SMN. These findings demonstrate that Mib1 ubiquitinates and catalyzes the degradation of SMN, and thus represents a novel therapeutic target for spinal muscular atrophy. (2) Characterization of the effects of histone deacetylase inhibition in SMA muscle. During muscle atrophy, the E3 ligase atrogenes, atrogin-1 and muscle ring finger 1 (MuRF1), mediate muscle protein breakdown through the ubiquitin proteasome system. Atrogene expression can be induced by various upstream regulators. During acute denervation, they are activated by myogenin, which is in turn regulated by histone deacetylases 4 and 5. We showed that atrogenes are induced in SMA model mice and in SMA patient muscle in association with increased myogenin and histone deacetylase-4 (HDAC4) expression. This activation during both acute denervation and SMA disease progression is suppressed by treatment with a histone deacetylase inhibitor;however, this treatment has no effect when atrogene induction occurs independently of myogenin. These results indicate that myogenin-dependent atrogene induction is amenable to pharmacological intervention with histone deacetylase inhibitors and help to explain the beneficial effects of these agents on SMA and other denervating diseases. (3) Characterization of the effects of IGF-1 in an animal model of SBMA. Our recent studies have demonstrated that IGF-1 reduces the mutant androgen receptor toxicity through activation of Akt in vitro, and spinal and bulbar muscular atrophy transgenic mice that also overexpress a non-circulating muscle isoform of IGF-1 have a less severe phenotype. Here we sought to establish the efficacy of daily intraperitoneal injections of mecasermin rinfabate, recombinant human IGF-1 and IGF-1 binding protein 3, in a transgenic mouse model expressing the mutant androgen receptor with an expanded 97 glutamine tract. The study was done in a controlled, randomized, blinded fashion, and in order to reflect the clinical settings the injections were started after the onset of disease manifestations. The treatment resulted in increased Akt phosphorylation and reduced mutant androgen receptor aggregation in muscle. In comparison to vehicle-treated controls, IGF-1 treated transgenic mice showed improved motor performance, attenuated weight loss, and increased survival. Our results suggest that peripheral tissue can be targeted to improve the spinal and bulbar muscular atrophy phenotype and indicate that IGF-1 warrants further investigation in clinical trials as a potential treatment for this disease.

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Pourshafie, Naemeh; Lee, Philip R; Chen, Ke-Lian et al. (2016) MiR-298 Counteracts Mutant Androgen Receptor Toxicity in Spinal and Bulbar Muscular Atrophy. Mol Ther 24:937-45
Fischbeck, Kenneth H (2016) Spinal and Bulbar Muscular Atrophy Overview. J Mol Neurosci 58:317-20
Hjelm, B E; Grunseich, C; Gowing, G et al. (2016) Mifepristone-inducible transgene expression in neural progenitor cells in vitro and in vivo. Gene Ther 23:424-37
Bott, Laura C; Salomons, Florian A; Maric, Dragan et al. (2016) The polyglutamine-expanded androgen receptor responsible for spinal and bulbar muscular atrophy inhibits the APC/C(Cdh1) ubiquitin ligase complex. Sci Rep 6:27703
Foran, Emily; Kwon, Deborah Y; Nofziger, Jonathan H et al. (2016) CNS uptake of bortezomib is enhanced by P-glycoprotein inhibition: implications for spinal muscular atrophy. Neurobiol Dis 88:118-24
Bott, Laura C; Badders, Nisha M; Chen, Ke-Lian et al. (2016) A small-molecule Nrf1 and Nrf2 activator mitigates polyglutamine toxicity in spinal and bulbar muscular atrophy. Hum Mol Genet 25:1979-1989
Scaramuzzino, Chiara; Casci, Ian; Parodi, Sara et al. (2015) Protein arginine methyltransferase 6 enhances polyglutamine-expanded androgen receptor function and toxicity in spinal and bulbar muscular atrophy. Neuron 85:88-100
Pripuzova, Natalia S; Getie-Kebtie, Melkamu; Grunseich, Christopher et al. (2015) Development of a protein marker panel for characterization of human induced pluripotent stem cells (hiPSCs) using global quantitative proteome analysis. Stem Cell Res 14:323-38
Bricceno, Katherine V; Martinez, Tara; Leikina, Evgenia et al. (2014) Survival motor neuron protein deficiency impairs myotube formation by altering myogenic gene expression and focal adhesion dynamics. Hum Mol Genet 23:4745-57
Renvoisé, Benoît; Chang, Jaerak; Singh, Rajat et al. (2014) Lysosomal abnormalities in hereditary spastic paraplegia types SPG15 and SPG11. Ann Clin Transl Neurol 1:379-389

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