Related Experiment Video
Updated: Sep 6, 2025
Assay to Measure Nucleocytoplasmic Transport in Real Time within Motor Neuron-like NSC-34 Cells
Published on: May 16, 2017
Myelin loss in C9orf72 hexanucleotide expansion carriers
Sònia Sirisi1,2, Marta Querol-Vilaseca1,2, Oriol Dols-Icardo1,2
1Memory Unit, Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
The C9orf72 gene expansion, a common cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), is linked to myelin loss in the frontal cortex. This myelin damage may stem from oligodendrocyte dysfunction or the presence of phosphorylated TDP-43 in these cells.
Area of Science:
- Neuroscience
- Genetics
- Neuropathology
Background:
- The C9orf72 hexanucleotide repeat expansion is the most common genetic cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS).
- Phosphorylated TAR DNA-binding protein 43 (pTDP-43) accumulation is a key neuropathological hallmark in these disorders.
- While glial roles in neurodegeneration are recognized, oligodendrocyte involvement remains less understood.
Purpose of the Study:
- To investigate glial cell expression patterns in the frontal cortex of C9orf72-associated FTLD (C9-FTLD) and C9-FTLD/ALS patients.
- To compare myelin basic protein (MBP) levels in cerebrospinal fluid (CSF) from an independent FTD cohort.
- To explore the relationship between myelin loss and pTDP-43 in the context of C9orf72 expansions.
Main Methods:
- Digital neuropathological analysis of human post-mortem frontal cortex samples (C9-FTLD, C9-FTLD/ALS, sporadic FTLD, and healthy controls).
- Immunohistochemical assessment of glial markers (GFAP, Iba1) and myelin marker (MBP).
- Measurement of MBP concentrations in CSF from a clinical FTD cohort.
Main Results:
- Increased GFAP and Iba1 immunoreactivity were observed in gray matter of C9 and sporadic FTLD cases compared to controls.
- A decrease in MBP immunoreactivity was found in both gray and white matter of the frontal cortex in C9 cases versus controls and sporadic FTLD.
- A negative correlation between MBP and pTDP-43 was noted in the white matter of C9 cases, alongside elevated CSF MBP levels in C9 and sporadic FTLD patients.
Conclusions:
- The C9orf72 expansion is associated with significant myelin loss in the frontal cortex.
- This myelin deficit may result from oligodendrocyte dysfunction or the presence of pTDP-43 within oligodendrocytes.
- Further understanding of these mechanisms is crucial for identifying therapeutic targets for C9orf72-related disorders.
