The bi-annual international conference on FTD that features content for both scientist/clinicians and caregivers has begun again.
In the pursuit of blood tests that can detect mutations responsible for FTD, Dr. Rosa Rademakers has found a disconnect between levels of blood markers for Chromosome 9 mutation orf72 and levels in brain tissue markers. This means that testing for this mutation’s severity won’t be possible through a relatively easy-to-obtain blood sample. Such may not be the case for other genetic mutations associated with FTD, but it is an important new point to guide the search for early detection methods.
Dr. Rademakers’ lab has done all sorts of work to elucidate how that C9orf72 gene can lead to the brain deterioration, and one important new clue is that homeobox genes, which work neuronal repair and regeneration, seem to respond to the C9orf72 abnormality. Do those homeobox (“HOX” if you want to google or pubmed search it) genes need a boost in order for patients to compensate for their dementia? These results are so fresh that they are being presented in posters at the conference, which often precedes their publication in a medical journal for 6-12 months.
International collaboration to consolidate progranulin mutation carriers (different chromosome and gene from C9orf72) has brought 555 mutation carriers DNA together for analysis – more to come in the future. The largest families with FTD have yielded the previously described progranulin, C9orf72, fused in sarcoma (FUS), MAPT (tau), CHMP2B, or valosin-containing protein (VCP) mutations. This is roughly 20% of known FTD cases followed in Antwerp.
The Mayo Clinic (Dr. Rademakers’ home base) has 170 brains from patients with TDP-43 proteinopathy (frequently a result of progranulin mutation), and whole-genome sequencing is under way. This has identified 2 new mutations related to the ALS-variant of FTD, a mutation on chromosome *10* in a gene that codes for protein optineurin (OPTN). A candidate gene under examination but NOT YET PROVEN to have a strong or likely causal association to FTD is KIF-17.
Dr. Christine van Broeckhoven from the Univ of Antwerp reported from her lab:
in their search for which genetic factors determine the earlier ages at onset of FTD, they have not seen a role for serum levels of progranulin protein. Instead, it seems that one particular part of the genome may be responsible for assigning a person’s onset age. The next steps are to correlate this with something more easily identifiable in either serum or cerebrospinal fluid (obtained through lumbar puncture).
Among cases with C9orf72 mutations, they report that short repeat sequences seem to be more associated with anticipation between generations, which is the phenomenon of a child having earlier onset age than an affected parent. This is significant as the opposite of what happens in a disease like Huntington’s, in which more repeats means earlier onset of illness. If you’re a genetics junkie, you may be interested to know that the degree of repeats affects the methylation status of the DNA processing.
another candidate gene, FLNC, makes protein filamin C. The expression of this gene is increased in TDP-43 patients, so it may be a secondary villain in taking down the integrity of cell structure and ability to communicate.
another candidate gene: VPS13C may work independent of the aforementioned genetic mutations. It’s been identified in a few families and some patients without family history. Dr. Stephanie Philtjens reported further on the clinical presentations of patients with this mutation. Onset ages were 62 years on average, with two cases manifesting in their early 40s. About half of patients were women, no gender bias. There is decreased VPS13C protein in patients with the mutation, but what the protein is normally doing in relation to preventing dementia remains unclear. There may be a link to Alzheimer’s disease as well. Genetics junkies may recall that CHMP2B is another gene for VPS, which has an established link to FTD.
work continues to understand how mutations in SQSTM1 lead to ALS or other neurodegenerative disorders. This one doesn’t have a single association to illness; variants in the mutation lead patients to different fates.
Carrying on from the SQSTM1 theme above, Dr. Paul Taylor described ongoing work on the association between inclusion body myopathy (IBM), Paget’s disease of bone, and familial cases of ALS. Matrin 3 mutations can be responsible for this presentation, but Dr. Taylor has been working most on VCP. The protein will ordinarily act as the remodeler of multimeric complexes. That’s a mouthful that I can really only translate for you as helping to keep working surfaces within the cell functioning to traffic proteins appropriately. In the presence of the mutation, cells pocket TDP-43. For genetics junkies, VCP in this context is gumming up hnRNPA species 1 and 2B1.
The exciting part of this work is the similarity of glycine-rich segments of the hnRNPAs to yeast prions. You may have heard of prions before, in the context of mad cow disease or Creutzfeld-Jakob disease. Neil Cashman out here at UBC has been arguing in favor of a prion mechanism turning dementias (not just FTD) on at a certain point in life, based on genetic vulnerabiltiies and environmental exposures. Dr. Taylor explained that the prion-like portions of the hnRNPAs may be the place where that switching-on may transpire, resulting immediately (at least in his videos) of key proteins precipitating out of solution into granules loaded with proteinopathy! The good news is that the switch can go in the other direction, OFF, so his lab is hot on the trail of how to control that switch. In a Petri dish, they can use a laser to disassemble the granules, but the presence of VCP locks the switch to ON.