sirolimus and Osteitis-Deformans

p62/SQSTM1, encoded by gene

Topics: Animals; Atherosclerosis; Autophagy; Humans; Neurodegenerative Diseases; Osteitis Deformans; Protein Domains; Sequestosome-1 Protein; Signal Transduction; Tumor Suppressor Proteins

Mutations in the valosin containing protein (VCP) gene cause hereditary Inclusion body myopathy (hIBM) associated with Paget disease of bone (PDB), frontotemporal dementia (FTD), more recently termed multisystem proteinopathy (MSP). Affected individuals exhibit scapular winging and die from progressive muscle weakness, and cardiac and respiratory failure, typically in their 40s to 50s. Histologically, patients show the presence of rimmed vacuoles and TAR DNA-binding protein 43 (TDP-43)-positive large ubiquitinated inclusion bodies in the muscles. We have generated a VCPR155H/+ mouse model which recapitulates the disease phenotype and impaired autophagy typically observed in patients with VCP disease. Autophagy-modifying agents, such as rapamycin and chloroquine, at pharmacological doses have previously shown to alter the autophagic flux. Herein, we report results of administration of rapamycin, a specific inhibitor of the mechanistic target of rapamycin (mTOR) signaling pathway, and chloroquine, a lysosomal inhibitor which reverses autophagy by accumulating in lysosomes, responsible for blocking autophagy in 20-month old VCPR155H/+ mice. Rapamycin-treated mice demonstrated significant improvement in muscle performance, quadriceps histological analysis, and rescue of ubiquitin, and TDP-43 pathology and defective autophagy as indicated by decreased protein expression levels of LC3-I/II, p62/SQSTM1, optineurin and inhibiting the mTORC1 substrates. Conversely, chloroquine-treated VCPR155H/+ mice revealed progressive muscle weakness, cytoplasmic accumulation of TDP-43, ubiquitin-positive inclusion bodies and increased LC3-I/II, p62/SQSTM1, and optineurin expression levels. Our in vitro patient myoblasts studies treated with rapamycin demonstrated an overall improvement in the autophagy markers. Targeting the mTOR pathway ameliorates an increasing list of disorders, and these findings suggest that VCP disease and related neurodegenerative multisystem proteinopathies can now be included as disorders that can potentially be ameliorated by rapalogs.

Topics: Animals; Apoptosis; Autophagy; Cell Cycle Proteins; Cell Line; Chloroquine; Disease Models, Animal; DNA-Binding Proteins; Eye Proteins; Frontotemporal Dementia; Gene Knock-In Techniques; Humans; Intercellular Signaling Peptides and Proteins; Male; Membrane Transport Proteins; Mice; Muscle, Skeletal; Myoblasts; Osteitis Deformans; Peptides; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Ubiquitin

Pathological phenotypes in inclusion body myopathy (IBM) associated with Paget disease of the bone (PDB), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) (IBMPFD/ALS) include defective autophagosome and endosome maturation that result in vacuolation, weakness and muscle atrophy. The link between autophagy and IBMPFD/ALS pathobiology has been poorly understood. We examined the AKT-FOXO3 and MTOR pathways to characterize the regulation of autophagy in IBMPFD/ALS mouse muscle. We identified a defect in MTOR signaling that results in enhanced autophagosome biogenesis. Modulating MTOR signaling may therefore be a viable therapeutic target in IBMPFD/ALS.

Topics: Adenosine Triphosphatases; Animals; Autophagy; Cell Cycle Proteins; Disease Models, Animal; Frontotemporal Dementia; Humans; Mice; Muscle Weakness; Mutant Proteins; Myositis, Inclusion Body; Osteitis Deformans; Phagosomes; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Valosin Containing Protein