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51/100

✓ Peer-reviewed alzhub usefulness score 51 out of 100. Caregiving

Topic: Brain proteins, microglia and lab models

Hexanucleotide repeat expansion in C9ORF72 is the most common genetic cause of frontotemporal dementia and motor neuron disease. One consequence of the mutation is the formation of different potentially toxic polypeptides composed of dipeptide repeats (DPR) (poly-GA, -GP, -GR, -PA, -PR) generated by repeat-associated non-ATG (RAN) translation. While previous studies focusing on poly-GA pathology have failed to detect any clinico-pathological correlations in C9ORF72 mutation cases, recent data from animal and cell culture models suggested that it may be only specific DPR species that are toxic and only when accumulated in certain intracellular compartments. Therefore, we performed a systematic clinico-pathological correlative analysis with counting of actual numbers of distinct types of inclusion (neuronal cytoplasmic and intranuclear inclusions, dystrophic neurites) for each DPR protein in relevant brain regions (premotor cortex, lower motor neurons) in a cohort of 35 C9ORF72 mutation cases covering the clinical spectrum from those with pure MND, mixed FTD/MND and pure FTD. While each DPR protein pathology had a similar pattern of anatomical distribution, the total amount of inclusions for each DPR protein varied remarkably (poly-GA > GP > GR > PR/PA), indicating that RAN translation seems to be more effective from sense than from antisense transcripts. Importantly, with the exception of moderate associations for the amount of poly-GA-positive dystrophic neurites with degeneration in the frontal cortex and total burden of poly-GA pathology with disease onset, no relationship was identified for any other DPR protein pathology with degeneration or phenotype. Biochemical analysis revealed a close correlation between insoluble DPR protein species and numbers of visible inclusions, while we did not find any evidence for the presence of soluble DPR protein species. Thus, overall our findings strongly argue against a role of DPR protein aggregation as major and exclusive pathomechanism in C9ORF72 pathogenesis. However, this does not exclude that DPR protein formation might be essential in C9ORF72 pathogenesis in interplay with other consequences associated with the C9ORF72 repeat expansion.

Key findings

While previous studies focusing on poly-GA pathology have failed to detect any clinico-pathological correlations in C9ORF72 mutation cases, recent data from animal and cell culture models suggested that it may be only specific DPR species that are toxic and only when accumulated in certain intracellular compartments.
Biochemical analysis revealed a close correlation between insoluble DPR protein species and numbers of visible inclusions, while we did not find any evidence for the presence of soluble DPR protein species.
Thus, overall our findings strongly argue against a role of DPR protein aggregation as major and exclusive pathomechanism in C9ORF72 pathogenesis.
However, this does not exclude that DPR protein formation might be essential in C9ORF72 pathogenesis in interplay with other consequences associated with the C9ORF72 repeat expansion.

Why it matters

In 35 C9ORF72 mutation cases, this study counted different dipeptide repeat protein inclusions in the brain and found their amounts varied, with no evidence of soluble forms. It is a pathology study of a genetic cause of frontotemporal dementia and motor neuron disease and does not test any treatment or cure.

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Study details

Evidence strengthModerate

How this study scored 51/100

Published in a leading specialty journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.

Component	Points	Why
Journal tier	9 / 10	Tier 2 — leading specialty journal (Acta neuropathologica)
Journal's citation record	3 / 4	Acta Neuropathologica: journal h-index 287 (OpenAlex, 2026-10-29)
Study design	0 / 12	No study design recorded — scores zero, not guessed (not stated in the record — scored 0)
Strength of evidence	3 / 5	Rated “moderate” in our summary
Peer-review validation	10 / 10	Peer-reviewed. Published as an article in a named peer-reviewed journal.
How recent	1 / 5	2015 — within 20 year(s) of the newest study here
Sample size	0 / 4	Participant count not stated — scores zero (not stated in the record — scored 0)
Effect reported	0 / 3	No effect size reported — scores zero (not stated in the record — scored 0)
Studied in people	0 / 3	Not stated whether this was studied in people — scores zero (not stated in the record — scored 0)
Randomised / blinded	0 / 2	No randomisation or blinding stated — scores zero (not stated in the record — scored 0)
Times cited	5 / 7	Cited 232 times (OpenAlex, 2026-10-10)
Citations per year	3 / 5	17.8 citations a year over 13 year(s) since 2015
Impact for its field and year	4 / 6	Cited 14.2× the average for papers of its field and year (OpenAlex FWCI)
Cited by studies here	2 / 6	Cited by 9 other studies in this library
Still being cited	2 / 4	Cited 28 times in 2024–2026 (2026 still in progress; OpenAlex)
Senior author's track record	3 / 4	Last-listed author Manuela Neumann: h-index 90 (OpenAlex, whole career)
Institution's track record	1 / 3	University of British Columbia: institution h-index 1,424 (OpenAlex)
Multi-centre collaboration	3 / 3	OpenAlex lists 12 institution(s) in 4 countries
Indexed in PubMed	2 / 2	Indexed in PubMed (PMID 26374446)
Free to read	0 / 2	Behind a paywall — scores zero
Total	51 / 100	—

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Read the original

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Cite this study APA, Vancouver, BibTeX · download .bib or .ris

Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.

APA 7th

Mackenzie, I. R., Frick, P., Grässer, F. A., Gendron, T. F., Petrucelli, L., Cashman, N. R., et al. (2015). Quantitative analysis and clinico-pathological correlations of different dipeptide repeat protein pathologies in C9ORF72 mutation carriers. Acta neuropathologica. https://doi.org/10.1007/s00401-015-1476-2

Vancouver

Mackenzie IR, Frick P, Grässer FA, Gendron TF, Petrucelli L, Cashman NR, et al. Quantitative analysis and clinico-pathological correlations of different dipeptide repeat protein pathologies in C9ORF72 mutation carriers. Acta neuropathologica. 2015. doi:10.1007/s00401-015-1476-2. PMID: 26374446.

BibTeX

@article{mackenzie2015-26374446,
  author  = {Mackenzie, I. R. and Frick, P. and Grässer, F. A. and Gendron, T. F. and Petrucelli, L. and Cashman, N. R. and Edbauer, D. and Kremmer, E. and others},
  title   = {{Quantitative analysis and clinico-pathological correlations of different dipeptide repeat protein pathologies in C9ORF72 mutation carriers}},
  journal = {Acta neuropathologica},
  year    = {2015},
  doi     = {10.1007/s00401-015-1476-2},
  pmid    = {26374446},
  url     = {https://doi.org/10.1007/s00401-015-1476-2}
}

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