2020 Research Grant Propoosal Announcement
The NIH-funded Rare Diseases Clinical Research Network is conducting an online research survey to understand the impacts of Covid-19 on the rare disease community.
To better understand how individuals with rare diseases and their families are impacted by the COVID-19 pandemic, the NIH-funded Rare Diseases Clinical Research Network developed a twenty minute online research survey from home. This survey will provide an opportunity for rare disease patients and caregivers to share their experiences and help researchers learn more about community needs during a time of crisis. Learn more about this survey by clicking here.
Deubiquitinase USP7 contributes to the pathogenicity of spinal and bulbar muscular atrophy
We found that the deubiquitinase USP7 preferentially interacts with polyQ-expanded AR, and that lowering USP7 levels reduced mutant AR aggregation and cytotoxicity in cell models of SBMA. Moreover, USP7 knockdown suppressed disease phenotypes in SBMA and spinocerebellar ataxia type 3 (SCA3) fly models, and monoallelic knockout of Usp7 ameliorated several motor deficiencies in transgenic SBMA mice. USP7 overexpression resulted in reduced AR ubiquitination, indicating the direct action of USP7 on AR. To learn more, click here.
Split hand and motor axonal hyperexcitability in spinal and bulbar muscular atrophy
Split hand is not specific to ALS and can be caused by the peripheral mechanism alone in SBMA, whereas the effect of upper motor neuron lesion cannot be excluded in ALS. Our results also suggest that SBMA and ALS share common axonal excitability changes; increased nodal persistent sodium and reduced potassium currents that may accelerate motor neuronal death and differently affect axons-innervating different muscles. Ion channel modulators could be a therapeutic option for both SBMA and ALS. To learn more, click here.
Disease mechanism, biomarker and therapeutics for spinal and bulbar muscular atrophy (SBMA)
In the central nervous system, lower motor neurons are selectively affected, whereas pathology of patients and animal models also indicates involvement of skeletal muscle including loss of fasttwitch type 2 fibres and increased slow-twitch type 1 fibres, together with a glycolytic-to-oxidative metabolic switch. Evaluation of muscle and fat using MRI, in addition to biochemical indices such as serum creatinine level, are promising biomarkers to track the disease progression. The serum level of creatinine starts to decrease before the onset of muscle weakness, followed by the emergence of hand tremor, a prodromal sign of the disease. Androgen-dependent nuclear accumulation of the polyglutamine-expanded AR is an essential step in the pathogenesis, providing therapeutic opportunities via hormonal manipulation and gene silencing with antisense oligonucleotides. Animal studies also suggest that hyperactivation of Src, alteration of autophagy and a mitochondrial deficit underlie the neuromuscular degeneration in SBMA and provide alternative therapeutic targets. To learn more, click here.