Upstream pathogenesis in familial and sporadic frontotemporal dementia and motor neuron disease

University Of California, San Francisco, San Francisco CA

Investigators

Abstract

Frontotemporal dementia (FTD) and motor neuron disease (MND) are progressive neurodegenerative disorders linked to TDP-43 pathobiology. Little is known about upstream pathogenesis, especially in sporadic disease. The overarching model we seek to test in this R01 renewal is that genetic and sporadic forms of FTD/MND-TDP converge upstream of TDP-43 mislocalization and aggregation. To evaluate this hypothesis, we will study post-mortem brain tissue from patients with C9orf72-associated and sporadic FTLD/MND-TDP, mining a unique dataset assembled during the previous cycle using a novel multiplexed immunofluorescence platform. In Aims 1-2, we will deeply characterize the interaction between C9orf72- associated dipeptide repeat protein inclusions and TDP-43 and seek evidence for TDP-43 inclusions with similar characteristics in sporadic FTD/MND. In Aim 3, we will use biochemical and proteomic methods to seek novel dipeptide repeat protein and TDP-43 interaction partners, leveraging a rare cohort of patients with C9orf72-FTD/MND who show profound behavioral deficits despite minimal TDP-43 pathology and comparing them to patients with a high TDP-43 aggregate burden. In all aims, we will seek to correlate quantitative neuropathological variables with clinical symptom severity, functional status, and neurodegeneration severity. Collectively, these human tissue-based studies are expected to clarify the disease-relevance of emerging candidate upstream pathogenic events and to uncover and validate novel features using complementary tissue-based and bioinformatic approaches. This fundamental information has the potential to identify new therapeutic targets for evaluation in other experimental systems or in human clinical trials.