The neurodegenerative proteopathies—a family that includes Huntington disease (HD), Alzheimer disease (AD), Parkinson disease (PD), and several spinocerebellar ataxias (SCAs)—are etiologically heterogeneous but share two striking commonalities: 1) each involves the accumulation of a particular disease- related protein, and 2) although the disease-related proteins are ubiquitously expressed, each disease affects one brain region or cell type first, and then ramifies to other brain regions. Many groups, including ours, are studying ways to reduce levels of the relevant disease-related protein, such as huntingtin (in HD), a-synuclein (in PD), or Ab (in AD). So far, however, regional vulnerability has not been thoroughly investigated, and lack of understanding of its causes could cause protein-level-reducing treatments to fail. We learned this through studying SCA1, which is caused by expansion of a CAG repeat in ATAXIN1, which encodes a polyglutamine (polyQ) tract in the protein ATXN1 (Atxn1 is the mouse version of the protein). In SCA1, the presenting symptom is ataxia because the first brain region to become dysfunctional is the cerebellum. Eventually, other regions succumb to the disease, producing cognitive alterations and eventually death due to brainstem failure. We discovered that lowering Atxn1 levels in SCA1 knock-in mice (Atxn1154Q/+) improves cerebellar function, but not cognition and that loss of Atxn1 function leads to AD-like hippocampal degeneration by elevating Bace1 and increasing Ab production. Clearly, then, we need to consider regional or cell-type vulnerability to avoid relieving pathogenesis in one region while inducing new pathology in another. We had already learned that the polyQ expansion enhances Atxn1's interactions with the transcriptional repressor Capicua (Cic), which leads to hyper-repression of Cic target genes. In an SCA1 transgenic mouse model that expresses expanded human ATXN1 only in Purkinje cells, inserting additional mutations (V591A and S602D) into the expanded ATXN1 allele to block its interaction with Cic restores motor coordination and prevents Purkinje cell pathology. In the SCA1 knock-in mice, however, blocking the Atxn1-Cic interaction with these same mutations only partially improved motor coordination, had no effect on hippocampal deficits, and only a small effect on survival; these results indicate that either cerebellar cell types besides Purkinje cells or regions beyond the cerebellum contribute to incoordination (which we will investigate in Aim 1) and that interactors besides Cic are important in brain regions outside the cerebellum (to be investigated in Aim 2). We also discovered that increasing levels of Atxn1's paralog, Ataxin1-Like (Atxn1L), which compensates for many of Atxn1's activities, improves cerebellar function in SCA1 knock-in mice (the groundwork for Aim 3, where we will investigate the effects of increasing Atxn1L on other brain regions). We propose that understanding regional v...