C9orf72 loss-of-function: a trivial, stand-alone or additive mechanism in C9 ALS/FTD?
- PDF / 3,078,703 Bytes
- 19 Pages / 595.276 x 790.866 pts Page_size
- 47 Downloads / 138 Views
REVIEW
C9orf72 loss‑of‑function: a trivial, stand‑alone or additive mechanism in C9 ALS/FTD? Elke Braems1,2 · Bart Swinnen1,2,3 · Ludo Van Den Bosch1,2 Received: 14 June 2020 / Revised: 28 July 2020 / Accepted: 13 August 2020 © The Author(s) 2020
Abstract A repeat expansion in C9orf72 is responsible for the characteristic neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in a still unresolved manner. Proposed mechanisms involve gain-of-functions, comprising RNA and protein toxicity, and loss-of-function of the C9orf72 gene. Their exact contribution is still inconclusive and reports regarding loss-of-function are rather inconsistent. Here, we review the function of the C9orf72 protein and its relevance in disease. We explore the potential link between reduced C9orf72 levels and disease phenotypes in postmortem, in vitro, and in vivo models. Moreover, the significance of loss-of-function in other non-coding repeat expansion diseases is used to clarify its contribution in C9orf72 ALS/FTD. In conclusion, with evidence pointing to a multiple-hit model, loss-of-function on itself seems to be insufficient to cause neurodegeneration in C9orf72 ALS/FTD. Keywords C9orf72 · Repeat expansion · Amyotrophic lateral sclerosis · Frontotemporal dementia · Loss-of-function · Neurodegeneration · Postmortem · In vitro · In vivo Abbreviations ALS Amyotrophic lateral sclerosis ASO Antisense oligonucleotide CNS Central nervous system DENN Differentially expressed in normal and neoplastic cells DPR Dipeptide repeat protein ER Endoplasmic reticulum FTD Frontotemporal dementia GEF Guanine exchange factor GOF Gain-of-function iPSC Induced pluripotent stem cell iPSN IPSC-derived neuron KD Knockdown * Ludo Van Den Bosch [email protected] 1
Department of Neurosciences, Experimental Neurology, and Leuven Brain Institute (LBI), KU Leuven-University of Leuven, 3000 Leuven, Belgium
2
Laboratory of Neurobiology, Experimental Neurology, Center for Brain and Disease Research, VIB, Campus Gasthuisberg, O&N4, Herestraat 49, PB 602, 3000 Leuven, Belgium
3
Department of Neurology, University Hospitals Leuven, 3000 Leuven, Belgium
KO Knockout LOF Loss-of-function MN Motor neurons RAN Repeat-associated non-ATG RBP RNA binding protein SMCR8 Smith–Magenis chromosome region 8 UTR Untranslated region WDR41 WD repeat-containing protein 41
Introduction A repeat expansion in the C9orf72 gene is associated with two neurodegenerative disorders, which represent the extremes of a disease spectrum: amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) [108]. In ALS, loss of motor neurons in the spinal cord, brainstem, and primary motor cortex causes muscle weakness. FTD is characterized by degeneration of cortical neurons in the frontal and temporal lobe resulting mainly in behavioral aberrations. Characteristic for both diseases is the large phenotypic variability, including the heterogeneous involvement of upper and/or lower motor neurons [90, 108]. In c
Data Loading...
