1. Sense-encoded poly-GR dipeptide repeat proteins correlate to neurodegeneration and uniquely co-localize with TDP-43 in dendrites of repeat-expanded C9orf72 amyotrophic lateral sclerosis
- Author
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Saberi, Shahram, Stauffer, Jennifer E, Jiang, Jie, Garcia, Sandra Diaz, Taylor, Amy E, Schulte, Derek, Ohkubo, Takuya, Schloffman, Cheyenne L, Maldonado, Marcus, Baughn, Michael, Rodriguez, Maria J, Pizzo, Don, Cleveland, Don, and Ravits, John
- Subjects
Acquired Cognitive Impairment ,Brain Disorders ,Neurosciences ,Dementia ,Rare Diseases ,ALS ,Neurodegenerative ,Neurological ,Aged ,Aged ,80 and over ,Amyotrophic Lateral Sclerosis ,Brain ,C9orf72 Protein ,Cell Nucleus ,Cytoplasm ,DNA Repeat Expansion ,DNA-Binding Proteins ,Dendrites ,Dipeptides ,Female ,Humans ,Male ,Middle Aged ,Nerve Degeneration ,Neuroglia ,Spinal Cord ,C9orf72 ,Hexanucleotide repeat expansions ,Amyotrophic lateral sclerosis ,Dipeptide repeat proteins ,Arginine-containing dipeptide repeat proteins ,Poly-GR ,Sense strand ,Antisense strand ,Nuclear pore complex and nucleocytoplasmic transport ,Clinical Sciences ,Neurology & Neurosurgery - Abstract
Hexanucleotide repeat expansions in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (C9 ALS). The main hypothesized pathogenic mechanisms are C9orf72 haploinsufficiency and/or toxicity from one or more of bi-directionally transcribed repeat RNAs and their dipeptide repeat proteins (DPRs) poly-GP, poly-GA, poly-GR, poly-PR and poly-PA. Recently, nuclear import and/or export defects especially caused by arginine-containing poly-GR or poly-PR have been proposed as significant contributors to pathogenesis based on disease models. We quantitatively studied and compared DPRs, nuclear pore proteins and C9orf72 protein in clinically related and clinically unrelated regions of the central nervous system, and compared them to phosphorylated TDP-43 (pTDP-43), the hallmark protein of ALS. Of the five DPRs, only poly-GR was significantly abundant in clinically related areas compared to unrelated areas (p
- Published
- 2018