TY - JOUR
T1 - Nuclear lamina invaginations are not a pathological feature of C9orf72 ALS/FTD
AU - Coyne, Alyssa N.
AU - Rothstein, Jeffrey D.
N1 - Funding Information:
This work was supported by the ALSA Milton Safenowitz Postdoctoral Fellowship (ANC), along with funding from NIH-NINDS (NS099114; NS094239; AG057623), Department of Defense, The Robert Packard Center for ALS Research Answer ALS Program, ALS Finding a Cure, ALS Association, Muscular Dystrophy Association, F Prime, and the Chan Zuckerberg Initiative.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - The most common genetic cause of familial and sporadic amyotrophic lateral sclerosis (ALS) is a GGGGCC hexanucleotide repeat expansion (HRE) in the C9orf72 gene. While direct molecular hallmarks of the C9orf72 HRE (repeat RNA foci, dipeptide repeat protein pathology) are well characterized, the mechanisms by which the C9orf72 HRE causes ALS and the related neurodegenerative disease frontotemporal dementia (FTD) remain poorly understood. Recently, alterations to the nuclear pore complex and nucleocytoplasmic transport have been accepted as a prominent pathomechanism underlying C9orf72 ALS/FTD. However, global disruptions to nuclear morphology and the nuclear lamina itself remain controversial. Here, we use a large number of induced pluripotent stem cell derived spinal neurons and postmortem human motor cortex sections to thoroughly examine nuclear morphology and nuclear lamina disruptions with light microscopy. In contrast to previous studies in artificial overexpression model systems, endogenous levels of the C9orf72 HRE do not increase the frequency of nuclear lamina invaginations. In addition, the C9orf72 HRE has no impact on overall nuclear shape and size. Notably, the frequency of nuclear Lamin B1 invaginations increases with cellular aging, independent of the C9orf72 HRE. Together, our data suggest that nuclear morphology is unaltered in C9orf72 ALS/FTD.
AB - The most common genetic cause of familial and sporadic amyotrophic lateral sclerosis (ALS) is a GGGGCC hexanucleotide repeat expansion (HRE) in the C9orf72 gene. While direct molecular hallmarks of the C9orf72 HRE (repeat RNA foci, dipeptide repeat protein pathology) are well characterized, the mechanisms by which the C9orf72 HRE causes ALS and the related neurodegenerative disease frontotemporal dementia (FTD) remain poorly understood. Recently, alterations to the nuclear pore complex and nucleocytoplasmic transport have been accepted as a prominent pathomechanism underlying C9orf72 ALS/FTD. However, global disruptions to nuclear morphology and the nuclear lamina itself remain controversial. Here, we use a large number of induced pluripotent stem cell derived spinal neurons and postmortem human motor cortex sections to thoroughly examine nuclear morphology and nuclear lamina disruptions with light microscopy. In contrast to previous studies in artificial overexpression model systems, endogenous levels of the C9orf72 HRE do not increase the frequency of nuclear lamina invaginations. In addition, the C9orf72 HRE has no impact on overall nuclear shape and size. Notably, the frequency of nuclear Lamin B1 invaginations increases with cellular aging, independent of the C9orf72 HRE. Together, our data suggest that nuclear morphology is unaltered in C9orf72 ALS/FTD.
KW - Amyotrophic Lateral Sclerosis
KW - C9orf72
KW - Frontotemporal Dementia
KW - Lamin B1
KW - Nuclear envelope
KW - Nuclear morphology
KW - Nuclear pore complex
KW - Nucleocytoplasmic transport
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U2 - 10.1186/s40478-021-01150-5
DO - 10.1186/s40478-021-01150-5
M3 - Article
C2 - 33741069
AN - SCOPUS:85102761785
SN - 2051-5960
VL - 9
JO - Acta Neuropathologica Communications
JF - Acta Neuropathologica Communications
IS - 1
M1 - 45
ER -