While some protein aficionados may believe that the only thing better than one peptide is a dipeptide, a study from the lab of Leonard Petrucelli (Mayo Clinic, USA) recently established that the expansion of double-dealing dipeptide repeats promotes the development of neurodegenerative disease via the disruption of heterochromatin structure and function.
The diseases in question, frontotemporal dementia and amyotrophic lateral sclerosis, are associated with a hexanucleotide repeat expansion in the chromosome 9 open reading frame 72 (C9orf72) gene and subsequent abnormal production of proteins composed of repeating dipeptides. As the specific contribution of these duplicitous dipeptides to disease pathogenesis remains unclear, Zhang and colleagues engineered mice to express a labeled one example of a dipeptide, a proline-arginine dipeptide repeat protein or poly(PR), via intracerebroventricular administration of adeno-associated viral vectors.
Here’s what the authors found when they doubled down on dipeptide repeat expansion:
expression promotes brain atrophy and loss of poly(PR)-positive neurons,
resulting in impaired motor function and memory
- Mice with higher poly(PR) levels suffer from early death, while lower poly(PR) levels permit higher survival rates, suggesting a dose-dependent toxicity
- The Poly(PR) protein binds to DNA and disrupts heterochromatin by increasing levels of repressive (H3K27me3) and permissive (H3K4me3) histone modifications, causing nuclear lamin invaginations, and abolishing heterochromatin protein 1α (HP1α) foci
- While subsequent
RNA-sequencing and quantitative PCR analyses demonstrated that heterochromatin
disruption prompts a surprising down-regulation of differentially expressed
genes, poly(PR) expression also provokes a
significant upregulation in repetitive element transcription and the
accumulation of double-stranded RNA
- Previous studies have established a link between the expression of repetitive elements to several neurodegenerative diseases and neurotoxicity
- Similar heterochromatic aberrations, repetitive element overexpression, and double-stranded RNA accumulation appear in brain tissues derived from human patients with C9orf72-related neurodegenerative disease
The authors now advocate for the development of therapeutic strategies for C9orf72-related neurodegenerative disease that focus on not one but two approaches: the rescue of heterochromatin abnormalities and inhibiting the abnormal expression of repetitive elements to boost neuron survival.
To discover more on the role of heterochromatin disruption in neurodegeneration and the danger of double-crossing dipeptide expansion head over to Science, February 2019.