"Despite underlying heterogeneity, 97% of ALS cases clear a DNA- and RNA-binding protein called TDP-43 from the nucleus and accumulate it in the cytoplasm, resulting in a loss of nuclear function," Dr. Alyssa Coyne of Johns Hopkins University School of Medicine in Baltimore told Reuters Health by email.
"Newer work also shows changes to the nuclear pore," she said. "But if and how these two alterations were linked wasn't clear, nor were the processes that triggered these issues."
"We showed that induced pluripotent stem cell-derived motor neurons from patients with sporadic ALS showed some of the same nuclear pore alterations as those seen in the common familial form of the disease, C9orf72-ALS/FTD," she said. "In particular, these cells showed marked reductions in specific nucleoporins (Nups), proteins that comprise the NPC."
As reported in Science Translational Medicine, Dr. Coyne's team hypothesized that Nup alterations and the resulting loss of NPC function might lie upstream of the TDP-43 dysfunction and mislocalization widely observed in ALS, frontotemporal dementia, and related neurodegenerative diseases.
Indeed, a series of experiments revealed that CHMP7 was increased in the nuclei of spinal neurons derived from C9 and sporadic ALS-induced pluripotent stem cells, as well as in postmortem human motor cortex, before the emergence of Nup alterations.
Dr. Coyne explained, "We found an increase in CHMP7 from the nuclei of motor cortex neurons from C9 and sporadic ALS patients, but not in neurons from the occipital cortex. The cells didn't appear to be making additional CHMP7 but rather relocating it from the cytoplasm to the nucleus."
Additional experiments showed that CHMP7 wasn't responding to a damaged nuclear pore but that the increase in CHMP7 actually caused the nuclear pore issues, she said.
"The mislocalization of CHMP7 also led to the mislocalization and loss of nuclear function of TDP-43," she continued. This led to TDP-43 depletion from the nucleus and its subsequent accumulation in the cytoplasm - one of the earliest events in both familial and sporadic ALS.
The study also showed in human patient cells that antisense oligonucleotides (ASOs) can reduce CHMP7 proteins, and thereby repair the TDP-43 defect.
Summing up in the paper, Dr. Coyne and colleagues conclude, "Our data support a role for altered CHMP7-mediated Nup homeostasis as a prominent initiating pathological mechanism for familial and sporadic ALS and highlight the potential for CHMP7 as therapeutic target."
Dr. Leonard Petrucelli, professor of neuroscience and head of the neurodegenerative diseases lab at Mayo Clinic Jacksonville, commented on the study in an email to Reuters Health. "The findings not only provide novel mechanistic insight (into) CHMP7-mediated NPC injury and TDP-43 cytoplasmic mislocalization, but also demonstrate the concept that ASO-mediated CHMP7 knockdown is a promising therapeutic approach to treat both sporadic and C9orf72-associated ALS."
Areas of further study, according to Dr. Petrucelli, could include assessing the long-term potential side effects of CHMP7 knockdown, investigating the mechanism that regulates CHMP7 nuclear accumulation in ALS, and generating a mouse model expressing CHMP7-NES* to determine whether the model develops ALS-associated pathology and neurodegeneration.
SOURCE: https://bit.ly/3rOYweF Science Translational Medicine, online July 28, 2021.
By Marilynn Larkin
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