Cerebellar c9RAN proteins associate with clinical and neuropathological characteristics of C9ORF72 repeat expansion carriers
| Autor: | John A. Lucas, Keith A. Josephs, Clotilde Lagier-Tourenne, Jie Jiang, Tania F. Gendron, Amelia Robertson, Neill R. Graff-Radford, Monica Castanedes-Casey, Colleen S. Thomas, Marka van Blitterswijk, Beth K. Rush, Pamela Desaro, Joseph E. Parisi, Kevin B. Boylan, Julia E. Crook, David S. Knopman, Karen Overstreet, Dennis W. Dickson, Linda Rousseau, Ronald C. Petersen, Lillian M. Daughrity, Kevin F. Bieniek, Melissa E. Murray, Don W. Cleveland, Leonard Petrucelli, Rosa Rademakers, Bradley F. Boeve, Otto Pedraza, Dieter Edbauer |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Male
Pathology Cerebellum complications [Motor Neuron Disease] Messenger Hippocampus Dipeptide repeat proteins metabolism [Hippocampus] genetics [Cognition Disorders] pathology [Frontal Lobe] Cohort Studies Cognition C9orf72 complications [Frontotemporal Dementia] 80 and over pathology [Cerebellum] Amyotrophic lateral sclerosis genetics [Frontotemporal Dementia] Aged 80 and over DNA Repeat Expansion pathology [Motor Cortex] Motor Cortex Frontotemporal lobar degeneration metabolism [Cerebellum] Middle Aged 3. Good health Frontal Lobe metabolism [Motor Neuron Disease] genetics [Amyotrophic Lateral Sclerosis] metabolism [Frontal Lobe] medicine.anatomical_structure Frontotemporal Dementia metabolism [Frontotemporal Dementia] complications [Amyotrophic Lateral Sclerosis] Female genetics [Motor Neuron Disease] Frontotemporal dementia metabolism [Motor Cortex] medicine.medical_specialty complications [Cognition Disorders] Heterozygote pathology [Motor Neuron Disease] Neuropathological diagnosis Clinical Sciences Clinical Neurology Chromosome 9 and over metabolism [RNA Messenger] Pathology and Forensic Medicine Cellular and Molecular Neuroscience metabolism [Cognition Disorders] medicine Humans ddc:610 RNA Messenger Motor Neuron Disease pathology [Amyotrophic Lateral Sclerosis] Aged c9RAN proteins Original Paper Neurology & Neurosurgery C9orf72 Protein business.industry C9ORF72 repeat expansion metabolism [Amyotrophic Lateral Sclerosis] Amyotrophic Lateral Sclerosis Neurosciences Proteins Repeat-associated non-ATG translation medicine.disease genetics [Proteins] pathology [Hippocampus] Protein Biosynthesis pathology [Frontotemporal Dementia] RNA pathology [Cognition Disorders] Neurology (clinical) Human medicine C9orf72 protein human Trinucleotide repeat expansion business Cognition Disorders |
| Zdroj: | Acta neuropathologica 130(4), 559-573 (2015). doi:10.1007/s00401-015-1474-4 Acta neuropathologica, vol 130, iss 4 Acta neuropathologica Acta Neuropathologica |
| ISSN: | 0001-6322 |
| Popis: | Clinical and neuropathological characteristics associated with G4C2 repeat expansions in chromosome 9 open reading frame 72 (C9ORF72), the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, are highly variable. To gain insight on the molecular basis for the heterogeneity among C9ORF72 mutation carriers, we evaluated associations between features of disease and levels of two abundantly expressed “c9RAN proteins” produced by repeat-associated non-ATG (RAN) translation of the expanded repeat. For these studies, we took a departure from traditional immunohistochemical approaches and instead employed immunoassays to quantitatively measure poly(GP) and poly(GA) levels in cerebellum, frontal cortex, motor cortex, and/or hippocampus from 55 C9ORF72 mutation carriers [12 patients with ALS, 24 with frontotemporal lobar degeneration (FTLD) and 19 with FTLD with motor neuron disease (FTLD-MND)]. We additionally investigated associations between levels of poly(GP) or poly(GA) and cognitive impairment in 15 C9ORF72 ALS patients for whom neuropsychological data were available. Among the neuroanatomical regions investigated, poly(GP) levels were highest in the cerebellum. In this same region, associations between poly(GP) and both neuropathological and clinical features were detected. Specifically, cerebellar poly(GP) levels were significantly lower in patients with ALS compared to patients with FTLD or FTLD-MND. Furthermore, cerebellar poly(GP) associated with cognitive score in our cohort of 15 patients. In the cerebellum, poly(GA) levels similarly trended lower in the ALS subgroup compared to FTLD or FTLD-MND subgroups, but no association between cerebellar poly(GA) and cognitive score was detected. Both cerebellar poly(GP) and poly(GA) associated with C9ORF72 variant 3 mRNA expression, but not variant 1 expression, repeat size, disease onset, or survival after onset. Overall, these data indicate that cerebellar abnormalities, as evidenced by poly(GP) accumulation, associate with neuropathological and clinical phenotypes, in particular cognitive impairment, of C9ORF72 mutation carriers. Electronic supplementary material The online version of this article (doi:10.1007/s00401-015-1474-4) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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