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

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.