Review: Modelling the pathology and behaviour of frontotemporal dementia

Abstract

Frontotemporal dementia (FTD) encompasses a collection of clinically and pathologically diverse neurological disorders. Clinical features of behavioural and language dysfunction are associated with neurodegeneration, predominantly of frontal and temporal cortices. Over the past decade, there have been significant advances in the understanding of the genetic aetiology and neuropathology of FTD which have led to the creation of various disease models to investigate the molecular pathways that contribute to disease pathogenesis. The generation of in vivo models of FTD involves either targeting genes with known disease‐causative mutations such as GRN and C9orf72 or genes encoding proteins that form the inclusions that characterize the disease pathologically, such as TDP‐43 and FUS. This review provides a comprehensive summary of the different in vivo model systems used to understand pathomechanisms in FTD, with a focus on disease models which reproduce aspects of the wide‐ranging behavioural phenotypes seen in people with FTD. We discuss the emerging disease pathways that have emerged from these in vivo models and how this has shaped our understanding of disease mechanisms underpinning FTD. We also discuss the challenges of modelling the complex clinical symptoms shown by people with FTD, the confounding overlap with features of motor neuron disease, and the drive to make models more disease‐relevant. In summary, in vivo models can replicate many pathological and behavioural aspects of clinical FTD, but robust and thorough investigations utilizing shared features and variability between disease models will improve the disease‐relevance of findings and thus better inform therapeutic development.

Defective cyclophilin A induces TDP-43 proteinopathy: implications for amyotrophic lateral sclerosis and frontotemporal dementia

“…In fact, knocking down PPIA affected the expression of a number of TDP-43 target genes involved in pathways leading to neurodegeneration, including GRN. GRN has been found mutated in familial forms of FTD and the disease mechanism seems to be linked to GRN haploinsufficiency, as also confirmed in mouse models (Solomon et al, 2019). In the cortex of PPIA-/-mice, we found that GRN was downregulated, indicating that a GRN loss-of-function probably contributes to the development of an FTD phenotype in PPIA-/-mice.…”

“…In previous work we demonstrated that PPIA deficiency affected the expression of a number of TDP-43 target genes, including GRN, which is a major mutated gene in familiar FTD (Lauranzano et al, 2015). GRN mutations in patients result in haplo-insufficiency and GRN knock-out mice present an FTD-like phenotype with mild TDP-43 pathology (Solomon et al, 2019). We verified whether knocking out PPIA influenced GRN expression in the brain cortex of the mice.…”

“…Several mouse models of ALS/FTD have been generated targeting genes with known pathogenic roles but each one recapitulates only certain aspects of the human disease. For instance, TDP-43 pathology in mice is often absent or mild and is not always linked to neurodegeneration or behavioural phenotypes 62 . In TDP-43 mouse models overexpressing wild-type TDP-43 or diseaseassociated mutations, C-terminal TDP-43 fragments are detected at low levels or are absent 63 .…”

From basic research to the clinic: innovative therapies for ALS and FTD in the pipeline

“…These findings have contributed to shed light on the major biological processes altered in ALS and FTD/FTLD pathologies (Table 1) [29]. On the other hand, as the genes associated with these diseases were fleshed out, it was apparent that ALS and FTD share pathophysiological processes.…”

Frontotemporal lobar degenerations: from basic science to clinical manifestations

“…Appropriate disease models are useful tools for testing hypotheses relevant for disease pathogenesis of FTLDs and will be essential for probing the efficacy of therapeutic approaches once they have become available. The article by Solomon, Mitchell, Konrad, Vance and Mizielinska provides a comprehensive and critical review of the in vivo models of distinct forms of FTLDs with an emphasis on disease models that replicate neuropathological and behavioural aspects of the human disease. It is particularly useful that the authors discuss separately two large groups of FTLD models, the genetic models ( GRN , C9orf72 , CHMP2B , VCP , UBQLN2 , SQSTM1 ) and models whose primary aim is to recapitulate directly the pathology of FTLD‐TDP or FTLD‐FUS.…”