Progranulin and TMEM106B: when two become wan

Mutations in GRN, which encodes progranulin, are a common cause of familial frontotemporal dementia (FTD). FTD is a devastating disease characterised by neuronal loss in the frontal and temporal lobes that leads to changes in personality, behaviour and language. There are no effective treatments for this complex condition. TMEM106B is a well‐recognised risk factor for FTD caused by GRN mutation. While the specific relationship between progranulin and TMEM106B is unclear, it is well established that they are both required for correct lysosome function and trafficking. Elegant experiments have suggested that increased risk for FTD is due to elevated levels of TMEM106B (Nicholson et al, 2013; Gallagher et al, 2017). Therefore, recent work has explored the therapeutic potential of reducing TMEM106B levels, with initial results looking encouraging, as crossing a Grn‐deficient mouse to a Tmem106b knockout showed a rescue in FTD‐related behavioural defects and specific aspects of lysosome dysfunction (Klein et al, 2017). However, three independent studies in this issue report that completely removing Tmem106b from Grn knockout mice leads to clear exacerbation of phenotypes, causing severe motor deficits, neurodegeneration and enhanced lysosome abnormalities and gliosis. Remarkably, the double knockout mice also develop TDP‐43 pathology—a hallmark of FTD patients with GRN mutations that have not been consistently observed in either of the single knockouts. These concurrent publications that all reach the same surprising but definitive conclusion are a cautionary tale in the control of TMEM106B levels as a potential therapeutic for FTD. They also re‐ignite the debate as to whether loss or gain of TMEM106B function is critical for altering FTD risk

Specific biomarkers for C9orf72 FTD/ALS could expedite the journey towards effective therapies

A hexanucleotide repeat expansion in the C9orf72 gene is a common genetic cause of ALS and FTD. The repeats are translated into five different dipeptide repeat proteins (DPRs). In this issue, Lehmer et al (2017) demonstrate that one of these DPRs, poly(GP), can be measured in the CSF of individuals with C9orf72 mutations. In conjunction with the findings from another recent study (Gendron et al, 2017), these DPR biomarkers may prove to be extremely valuable in the quest for effective therapies for C9FTD/ALS

Relax, Don't RAN Translate It

The (GGGGCC)n repeat expansion in C9orf72, which is the most common cause of frontotemporal dementia and amyotrophic lateral sclerosis, is translated through repeat-associated non-AUG (RAN) translation. In this issue of Neuron, Cheng et al. (2019) report that the helicase DDX3X, which unwinds (or relaxes) RNA, suppresses RAN translation and toxicity

One target for amyotrophic lateral sclerosis therapy?

Repeat expansion mutations cause a range of developmental, neurodegenerative, and neuromuscular disorders. The repeat sequences generally comprise a 3– to 6–base pair repeat unit that expands above a critical threshold, leading to disease. Expanded repeats cause disease via a range of mechanisms, including loss of function of the repeat-containing protein and production of toxic repeat RNAs and proteins, making the disorders difficult to treat. In 2011, a hexanucleotide repeat expansion in the C9orf72 gene was identified as the most common cause of frontotemporal dementia and amyotrophic lateral sclerosis (termed c9FTD/ALS) (1, 2). On page 708 of this issue, Kramer et al. (3) report that targeting a single factor, Spt4, reduced production of C9orf72 repeat expansion–associated RNA and protein, and ameliorated neurodegeneration in model systems

Quantitative analysis of cryptic splicing associated with TDP-43 depletion

BACKGROUND: Reliable exon recognition is key to the splicing of pre-mRNAs into mature mRNAs. TDP-43 is an RNA-binding protein whose nuclear loss and cytoplasmic aggregation are a hallmark pathology in amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). TDP-43 depletion causes the aberrant inclusion of cryptic exons into a range of transcripts, but their extent, relevance to disease pathogenesis and whether they are caused by other RNA-binding proteins implicated in ALS/FTD are unknown. METHODS: We developed an analysis pipeline to discover and quantify cryptic exon inclusion and applied it to publicly available human and murine RNA-sequencing data. RESULTS: We detected widespread cryptic splicing in TDP-43 depletion datasets but almost none in another ALS/FTD-linked protein FUS. Sequence motif and iCLIP analysis of cryptic exons demonstrated that they are bound by TDP-43. Unlike the cryptic exons seen in hnRNP C depletion, those repressed by TDP-43 cannot be linked to transposable elements. Cryptic exons are poorly conserved and inclusion overwhelmingly leads to nonsense-mediated decay of the host transcript, with reduced transcript levels observed in differential expression analysis. RNA-protein interaction data on 73 different RNA-binding proteins showed that, in addition to TDP-43, 7 specifically bind TDP-43 linked cryptic exons. This suggests that TDP-43 competes with other splicing factors for binding to cryptic exons and can repress cryptic exon inclusion. CONCLUSIONS: Our quantitative analysis pipeline confirms the presence of cryptic exons during the depletion of TDP-43 but not FUS providing new insight into to RNA-processing dysfunction as a cause or consequence in ALS/FTD

C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia: gain or loss of function?

The molecular mechanisms that underlie chromosome 9 open reading frame 72 (C9orf72)-associated amyotrophic lateral sclerosis and frontotemporal dementia are rapidly emerging. Two potential disease mechanisms have been postulated - gain or loss of function. We provide an overview of recent advances that support or oppose gain-of-function and loss-of-function mechanisms

A novel synaptopathy-defective synaptic vesicle protein trafficking in the mutant CHMP2B mouse model of frontotemporal dementia

Mutations in the ESCRT-III subunit CHMP2B cause frontotemporal dementia (FTD) and lead to impaired endolysosomal trafficking and lysosomal storage pathology in neurons. We investigated the effect of mutant CHMP2B on synaptic pathology, as ESCRT function was recently implicated in the degradation of synaptic vesicle (SV) proteins. We report here that expression of C-terminally truncated mutant CHMP2B results in a novel synaptopathy. This unique synaptic pathology is characterised by selective retention of presynaptic SV trafficking proteins in aged mutant CHMP2B transgenic mice, despite significant loss of postsynaptic proteins. Furthermore, ultrastructural analysis of primary cortical cultures from transgenic CHMP2B mice revealed a significant increase in the number of presynaptic endosomes, while neurons expressing mutant CHMP2B display defective SV recycling and alterations to functional SV pools. Therefore, we reveal how mutations in CHMP2B affect specific presynaptic proteins and SV recycling, identifying CHMP2B FTD as a novel synaptopathy. This novel synaptopathic mechanism of impaired SV physiology may be a key early event in multiple forms of FTD, since proteins that mediate the most common genetic forms of FTD all localise at the presynapse