TY - JOUR
T1 - Insights into disease mechanisms and potential therapeutics for C9orf72-related amyotrophic lateral sclerosis/frontotemporal dementia
AU - Gagliardi, Delia
AU - Costamagna, Gianluca
AU - Taiana, Michela
AU - Andreoli, Luca
AU - Biella, Fabio
AU - Bersani, Margherita
AU - Bresolin, Nereo
AU - Comi, Giacomo Pietro
AU - Corti, Stefania
PY - 2020/12
Y1 - 2020/12
N2 - In 2011, a hexanucleotide repeat expansion (HRE) in the noncoding region of C9orf72 was associated with the most frequent genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The main pathogenic mechanisms in C9-ALS/FTD are haploinsufficiency of the C9orf72 protein and gain of function toxicity from bidirectionally-transcribed repeat-containing RNAs and dipeptide repeat proteins (DPRs) resulting from non-canonical RNA translation. Additionally, abnormalities in different downstream cellular mechanisms, such as nucleocytoplasmic transport and autophagy, play a role in pathogenesis. Substantial research efforts using in vitro and in vivo models have provided valuable insights into the contribution of each mechanism in disease pathogenesis. However, conflicting evidence exists, and a unifying theory still lacks. Here, we provide an overview of the recently published literature on clinical, neuropathological and molecular features of C9-ALS/FTD. We highlight the supposed neuronal role of C9orf72 and the HRE pathogenic cascade, mainly focusing on the contribution of RNA foci and DPRs to neurodegeneration and discussing the several downstream mechanisms. We summarize the emerging biochemical and neuroimaging biomarkers, as well as the potential therapeutic approaches. Despite promising results, a specific disease-modifying treatment is still not available to date and greater insights into disease mechanisms may help in this direction.
AB - In 2011, a hexanucleotide repeat expansion (HRE) in the noncoding region of C9orf72 was associated with the most frequent genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The main pathogenic mechanisms in C9-ALS/FTD are haploinsufficiency of the C9orf72 protein and gain of function toxicity from bidirectionally-transcribed repeat-containing RNAs and dipeptide repeat proteins (DPRs) resulting from non-canonical RNA translation. Additionally, abnormalities in different downstream cellular mechanisms, such as nucleocytoplasmic transport and autophagy, play a role in pathogenesis. Substantial research efforts using in vitro and in vivo models have provided valuable insights into the contribution of each mechanism in disease pathogenesis. However, conflicting evidence exists, and a unifying theory still lacks. Here, we provide an overview of the recently published literature on clinical, neuropathological and molecular features of C9-ALS/FTD. We highlight the supposed neuronal role of C9orf72 and the HRE pathogenic cascade, mainly focusing on the contribution of RNA foci and DPRs to neurodegeneration and discussing the several downstream mechanisms. We summarize the emerging biochemical and neuroimaging biomarkers, as well as the potential therapeutic approaches. Despite promising results, a specific disease-modifying treatment is still not available to date and greater insights into disease mechanisms may help in this direction.
KW - Amyotrophic lateral sclerosis
KW - C9orf72
KW - Dipeptide repeat proteins
KW - Downstream mechanisms
KW - RNA foci
KW - Therapeutic approaches
UR - http://www.scopus.com/inward/record.url?scp=85092126771&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85092126771&partnerID=8YFLogxK
U2 - 10.1016/j.arr.2020.101172
DO - 10.1016/j.arr.2020.101172
M3 - Review article
C2 - 32971256
AN - SCOPUS:85092126771
VL - 64
JO - Ageing Research Reviews
JF - Ageing Research Reviews
SN - 1568-1637
M1 - 101172
ER -