Islets in humans with Type 2 diabetes, and the brain in neurodegenerative disease, exhibit many common features, including: protein misfolding of amyloidogenic proteins, inflammation, activation of vascular endothelium and dedifferentiation. Islet amyloid polypeptide, encoded by the gene IAPP in humans, is the most aggregate-prone and toxic of known amyloidogenic proteins. To address the question, does IAPP misfolding-induced stress initiate the wide ranging changes in islets in T2D, we compared the transcriptome of islets of human IAPP transgenic mice before diabetes onset with islets from humans with T2D. Beta cell IAPP toxicity reproduces the transcriptome in T2D islets with prominent activation of inflammation and vascular endothelium, and beta cell dedifferentiation. In common with T2D and neurodegenerative diseases, these changes were mediated through activation of key injury response transcription factors NF-kB, STAT3, CTNNB1 and ESR1. We conclude that suppression of IAPP expression is a potentially disease modifying therapeutic intervention in T2D.

Huntington’s disease (HD) is the most common monogenic, neurodegenerative disease. Despite identifying the causal mutation over 20 years ago, there are no disease-modifying treatments currently available for HD patients. A recent genome wide association study has identified several potential genetic modifiers of HD, including FAN1, but validation and further mechanistic investigation is needed. To determine whether Fan1 is a modifier of HD and to elucidate the mechanisms involving Fan1 that hasten or delay HD onset, I crossed a Fan1 knockdown (Fan1-KD) mouse model with a knock-in model of HD with 140 CAG repeats. I found that Fan1-KD caused minimal effect on gene transcription, but a significant enrichment of oligodendrocyte and microglia genes was observed. Fan1-KD led to increased mutant huntingtin (mHtt) aggregates in the striatum of HD mice. Lastly, Fan1-KD lead to increased somatic mHtt CAG repeat instability in the liver at 6m, but not 12m, but showed minimal impact on somatic CAG repeat instability in the brain of HD mice. Our findings suggest that Fan1 may act as a modifier in HD by protecting oligodendrocytes from mHtt-induced toxicity and preventing a non-cell autonomous exacerbation of striatal pathology. I also helped characterize a novel full-length human huntingtin genomic mouse model, known as BAC-CAG, with roughly 120 uninterrupted CAG repeats. BAC-CAG mice show robust behavioral phenotypes, age-dependent striatal transcriptionopathy, nuclear accumulation of mHTT and age-dependent increase in somatic mHTT CAG repeat instability. We also demonstrate that indices of somatic mHTT CAG repeat instability in the cortex and striatum correlate to activity/sleep-related behavioral deficits in BAC-CAG mice. Together, my results provide novel mechanistic insights into recently identified modifiers of HD age of onset.

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