Introduction
Frontotemporal dementia (FTD) is a neurodegenerative disease characterized by atrophy in the frontal lobe and temporal lobe. Second only to Alzheimer's disease in prevalence, FTD accounts for 20% of pre-senile dementia cases. Symptoms can begin to appear on average around 45 to 65 years of age, regardless of gender. The most common symptoms include significant changes in social and personal behavior, as well as a general blunting of emotions.
Amyotrophic Lateral Sclerosis (ALS) is a debilitating disease with varied etiology characterized by rapidly progressive weakness, muscle atrophy and fasciculations, muscle spasticity, difficulty speaking (dysarthria), difficulty swallowing (dysphagia), and difficulty breathing (dyspnea). ALS has mainly been described as a neurological disorder that affects the motor system, but is now recognized as a multisystem neurodegenerative disease due to the fact that other than motor areas of the brain undergo degeneration.
Even though FTD and ALS come across as distinct progressive disorders, there is increasing evidence of the fact that they share some clinical, neuropathological and genetic features.
FTD and ALS: a tale of two deseases. 2011
Description of the genetic mutations
Mutation in the gene C9orf72 is the most common genetic defect underlying this two deseases. The mutation consist of a hexanucleotide repeat expansion of the six letter string of nucleotides GGGGCC in a noncoding region (intron 1). In a normal person, there are up to 30 repeats of this hexanucleotide, but aberrant expansions can result in hundreds or thousands repeats. It is known that the mutation interferes with normal expression of the protein made by C9orf72 , however the function of that protein is unknown. This mutation has been found in at least 8% of sporadic ALS and FTD cases and more than 40% of hereditary ALS and FTD cases.
Atypical, slowly progressive behavioural variant frontotemporal dementia associated with C9ORF72 hexanucleotide expansion. 2012
A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. 2011
a | Genomic structure of C9orf72, showing coding (yellow) and noncoding (blue) exons, the position of the start codon (ATG) and stop codon (TAA), and the (GGGGCC)n repeat in the intronic region between exons 1a and 1b (star). b | PCR products of repeat-primed PCR reactions zoomed to 2,000 relative fluorescence units show stutter amplification in an FTD patient with the pathogenic expanded C9orf72 repeat (top) and an FTD patient with a normal C9orf72 repeat length (bottom). c | In addition to FTD and ALS pathology, all patients with the C9orf72 mutation show a unique pattern of ubiquitin-positive (brown) neuronal inclusions in the cerebellar granule layer and other specific neuroanatomical regions. d | RNA foci (red) in the nuclei of two lower motor neurons from a patient with FTD–ALS carrying the expanded GGGGCC repeat in C9orf72.
Hypothesis about neurodegenerative pathways
This type of mutation in C9orf72 suggests three possible desease mechanisms
- Loss of function: repeat expansion might impair expression of the gene product, but the dominant inheritance pattern observed in C9orf72 families makes a loss of function mechanism unlikely to be the sole cause of desease.
Intracellular inclusions
All of those proteins were detected in high molecular weight, insoluble material of cerebellar extracts from post mortem brains of C9orf72 patients. This is unusual because of the absence of TDP-43, protein present in neuronal inclusions of numerous neurodegenerative deseases, especially in FTD-ALS patients, in various central nervous system regions, including hippocampus, neocortex, and spinal cord.
TAR DNA-binding protein 43 in neurodegenerative disease. 2010
Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. 2006
While a unique feature of C9orf72 -related FTD-ALS is the abundance of starlike inclusions in the cerebellum and hippocampus, characterised by the presence of ubiquitin binding protein p62. All three dipeptides described above were found in these starlike inclusions, mostly poly-(Gly-Ala).
Furthermore, high molecular weight RAN products have been observed in brain homogenates from C9orf72 patients, due to antibodies producted against GGGGCC repeats, called anti-C9RANT , this kind of immunoreactivity was not found in other neurodegenerative diseases, or in peripheral tissues of c9FTD/ALS.
Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. 2013.
Conclusions
This studies show the importance of RAN translation in the common neurodegenerative pathway of some cases of FTD-ALS, and even if it remains to be determined how widespread this kind of pathology is, and wheter dipeptide proteins aggregates correlates with other clinically relevant central nervous system region, the specificity of C9orf72 aberrant products, like C9RANT , is a potential biomarker for this most common cause of FTD and ALS. The ability to detect C9RANT in individuals' cerebrospinal fluid may provide a valuable diagnostic and prognostic tool for identifying patients carrying the C9ORF72 repeat expansion and for then tracking the progression of the disease in these at-risk individuals.
Although it remains to be shown whether C9RANT is causing the cell death or toxicity associated with disease symptoms, this discovery offers a potential target to prevent neuronal loss in patients carrying this mutation.
The concept that abnormal proteins accumulate and can be toxic to cells is not new, in fact, tau protein forms tangles in Alzheimer's disease and alpha-synuclein forms clumps in Parkinson's disease. Just as new therapies are being developed to break down the protein aggregates associated with these diseases, developing a therapeutic strategy to target C9RANT aggregates may also prove beneficial.
