The Huntington's disease (HD) protein, huntingtin (HTT), is essential for early development. Because suppressing the expression of mutant HTT is an important approach to treat the disease, we must first understand the normal function of Htt in adults versus younger animals. Using inducible Htt knockout mice, we found that Htt depletion does not lead to adult neurodegeneration or animal death at >4 mo of age, which was also verified by selectively depleting Htt in neurons. On the other hand, young Htt KO mice die at 2 mo of age of acute pancreatitis due to the degeneration of pancreatic acinar cells. Importantly, Htt interacts with the trypsin inhibitor, serine protease inhibitor Kazal-type 3 (Spink3), to inhibit activation of digestive enzymes in acinar cells in young mice, and transgenic HTT can rescue the early death of Htt KO mice. These findings point out age-and cell type-dependent vital functions of Htt and the safety of knocking down neuronal Htt expression in adult brains as a treatment.Huntingtin | aging | degeneration | acinus | pancreas H untington's disease (HD) is caused by polyglutamine (polyQ) expansion in the N-terminal region of huntingtin (HTT). Despite its ubiquitous expression in the brain and body, mutant HTT causes selective neuronal degeneration as well as white matter atrophy in the brain (1-3). The neuronal degeneration is characterized by the preferential loss of neuronal cells in the striatum in the early disease stage and extensive neurodegeneration in a variety of brain regions in later disease stages. This progressive neurodegeneration is consistent with the late-onset neurological symptoms of HD, and age-dependent toxicity of mutant HTT is thus a characteristic of HD.HTT consists of 3,144 amino acids and is thought to be a scaffold protein that associates with a number of other proteins and participates in a wide range of cellular functions, including intracellular trafficking of a variety of proteins (1, 4). HTT is important during animal early development, as germ-line deletion of Htt leads to early death of mice at embryonic day 8.5 (5-7). A variety of HD animal models that express mutant HTT provide strong evidence for an age-dependent toxic gain of function of mutant HTT (8-12), and considerable efforts have been devoted to developing siRNA and antisense oligonucleotides to suppress the expression of mutant HTT in adult brains (13-15). Unfortunately, however, these approaches have also raised concerns that markedly suppressing HTT expression will lead to side effects by impairing HTT's normal function. To date, whether HTT has differential roles in early development and adulthood remains unknown. Clarifying these distinctions is vital if we are to develop a better strategy for treating HD.Using conditional Htt knockout mice to mate with transgenic CAG-CreER mice that express Cre-ER ubiquitously in the body and brain and transgenic mice expressing Cre-ER in neuronal cells, we generated inducible Htt knockout mice and found that loss of Htt in adult mouse brain does not cause ob...

Visible light-responsive dual-functional biodegradable mesoporous silica nanoparticles with drug delivery and lubrication enhancement were constructed by supramolecular interaction between azobenzene-modified mesoporous silica nanoparticles (bMSNs-AZO) and β-cyclodextrin-modified poly(2-methacryloyloxyethyl phosphorylcholine) (CD-PMPC). Visible...