Using Genetic Diversity to Manage Neurological Disease

Project Summary/Abstract
Understanding and treating genome abnormalities that lead to rare genetic neurodegenerative diseases such as
Niemann-Pick C1 globally managing cholesterol homeostasis, or APOE alleles impacting cholesterol
homeostasis in the brain triggering late-onset Alzheimer’s disease (LOAD), present a major challenge from both
basic science and clinical perspectives. We have developed a Gaussian process regression (GPR) based
machine learning (ML) approach that captures for the first time genomic variation in the population to understand
the spatial covariance (SCV) relationships contributing to sequence-to-function-to-structure relationships in the
individual. Genetic disease is fundamentally a problem of understanding the impact of altered folding
intermediates found in response to variation in the protein fold and how they are managed by proteostasis.
Proteostasis encompasses a broad range of chaperone and degradative components that manage the synthesis,
folding/stability and function of the protein fold in response to inherited and environmental stress and aging. The
general premise of this proposal is to develop a deep genome-based understanding of proteostasis that will
teach us how to manage genetic diseases triggered by folding stress. The rationale for this proposal is that
sparse genetic diversity found in the population, when used as a collective through application of GRP-ML
defined SCV relationships, can provide us on a residue-by-residue basis insight into the folding intermediates
that contribute to disease for the entire polypeptide sequence. The objective of this proposal is to understand
the role of proteostasis in managing this genetic diversity for the benefit of therapeutic intervention. We
hypothesize that management of the polypeptide fold of disease-causing variant proteins found in the population
by targeting the function of the multivalent Hsp40 and Hsp70 co-chaperone/chaperone branch (the Hsp70 axis)
of the proteostasis network will enable precision correction of misfolding phenotypes found in neurodegenerative
disease. Our approach will study the impact of variation in the Niemann Pick C1 (NPC1) gene. NPC1 is an
inherited, autosomal recessive, disorder characterized by the abnormal accumulation of unesterified cholesterol
and other lipids in late endosomal (LE) and lysosome (Ly) compartments of all cell types. The primary effect of
NPC1 variation results in early onset neurodegenerative disease in response to loss of cholesterol homeostasis.
In Aim 1 we will explore the ability of small molecules to allosterically regulate the activity of components of the
Hsp70 axis to retune the synthesis, folding/stability, trafficking and/or function of NPC1 variants. In Aim 2 we
will explore the molecular mechanism of action (MoA) of the Hsp70 axis components that are responsible for
enabling NPC1 variant correction. Completion of both aims will generate a comprehensive assessment of the
role of Hsp70 axis in NPC1 disease progression and will be used as a guide for advancement of a precision
medicine approach to reduce or prevent the onset of neurodegenerative disease triggered by genomic variation
in NPC1 population.

Grant Number: 5R01AG070209-05
NIH Institute/Center: NIH
Principal Investigator: William Balch