Impaired Protein Homeostasis in Neurodegenerative Diseases

Impaired Protein Homeostasis in Neurodegenerative Diseases

The below excerpt is from an article appearing in Select Science. Click on the title above to read the entire article. For a good explanation on autophagy, click on the link below the drawing to watch a video.

https://www.youtube.com/watch?v=PvnqzhtwGZU

“Learn how selective antibodies help decipher an impaired autophagy pathway in spino-bulbar muscular atrophy

Dr. Constanza Cortes, Assistant Professor in the Department of Neurology at Duke University School of Medicine, studies impaired protein homeostasis in polyglutamine diseases such as spino-bulbar muscular atrophy.

SS: What are polyglutamine diseases?

CC: Polyglutamine diseases are a family of inherited neurodegenerative disorders, all caused by expansion of a triplet-nucleotide, CAG, in the coding region of the affected genes. The most notable is Huntington’s Disease, caused by a CAG expansion in the huntingtin gene. Another polyglutamine disease is spino-bulbar muscular atrophy (SBMA), caused by a CAG expansion in the androgen receptor (AR) gene. As the CAG codon encodes for the amino acid glutamine, the resulting proteins all carry extended polyglutamine tracts, giving the name to this family of diseases.

I study SBMA, a neuromuscular condition that targets the skeletal muscle and motor neurons in the lower spinal cord. These express high levels of the mutant AR, that result in protein inclusions, accumulating in the nuclei of affected tissues. This suggests that impaired protein quality control may form the basis of the neurodegenerative phenotypes observed in SBMA.

SS: What is the focus of your research in spino-bulbar muscular atrophy (SBMA)?

CC: I focus on protein quality control mechanisms and investigate the role they may play in the pathogenesis of SBMA. Protein homeostasis (also known as proteostasis), is fundamental for the survival of neurons, and proteostasis dysfunction is a feature of many neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease. Understanding the mechanisms underlying proteostasis dysfunction and uncovering novel targets for rescuing these defects may yield important therapeutic targets for diseases associated with proteostasis failure.

SS: How does impaired protein homeostasis contribute to neurodegeneration in SBMA?

CC: I have uncovered a previously unreported periphery-to-CNS signaling network originating in skeletal muscle. Using a transgenic mouse model for a gene that’s a master regulator of cellular clearance and metabolism, conditionally expressed in the skeletal muscle, I have shown improved proteostasis in the CNS during normal aging. This suggests that maintaining skeletal muscle proteostasis during aging may yield important neuroprotective benefits in the aging brain.

In agreement with this, these muscle-specific proteostasis-activated mice perform significantly better in neurocognitive testing at 18 months of age compared to their age-matched control littermates. This suggests the existence of secreted signals originating in skeletal muscle and targeting the CNS, resulting in improved proteostasis control in the brain. My current work focuses on identifying those signals and testing their ability to rescue neurodegenerative ‘proteinopathies’, including Alzheimer’s disease….” For more, click on the heading at the top of this page.