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.

Possible new therapy for motor neuron diseases

The University of Sheffield published the following news release yesterday. As always, additional research is required, but the premise is interesting.

New discovery in motor neurone disease and dementia could pave the way to novel treatments

"... When this series of nucleotides is expanded and repeated multiple times, neurodegenerative diseases can occur. The expansions of the gene forms genetic material called ‘R-loops’ which make the DNA vulnerable to breakages. They found that accumulation of R-loops and increased DNA breakage in neurons lead to neurodegenerative diseases.

Our cells have their own repair toolkits specially designed to fix breaks in DNA, however, the products of the expansion over-activate a process called autophagy – a process that gets rid of misfolded or “unwanted” proteins.

The new study, jointly directed by Professor Sherif El-Khamisy from the University of Sheffield’s Department of MBB and Professor Mimoun Azzouz from SITraN at the University of Sheffield, published today (17 July 2017) in Nature Neuroscience, shows that the expansion driven over-activation of this process can degrade some of the very precious DNA toolkits, meaning the cells will eventually die.

“We were able to shut down the out-of-control degradation process, which runs down the cell’s ability to fix genomic breaks, using genetic techniques,” said Professor El-Khamisy.

“Even though the DNA was still damaged, the cells were able to cope and did not die. Discovering this new mechanism and its consequence is a significant step towards developing new therapies for motor neurone disease and other neurodegenerative conditions. ..."

Click on the title to read the entire article.