Neurodegeneration Challenge Network

Neurodegenerative disorders, like Alzheimer’s, Parkinson’s, ALS, and Huntington’s Disease, are a leading cause of death and disability worldwide. While there has been significant investment in neurodegenerative disease research, our understanding of the underlying cellular mechanisms and basic biology of most of these disorders is limited.

The CZI Neurodegeneration Challenge Network brings together experimental scientists from diverse research fields, along with computational biologists and physicians, to understand the fundamental biology of neurodegenerative disorders. Their shared aim is to develop new strategies for the treatment and prevention of neurodegenerative diseases.

We are excited to welcome our first cohort of Neurodegeneration Challenge Network grantees — 17 early career investigators and 9 collaborative science teams.

Scroll down to learn more about these investigators and their projects. To learn more about the Challenge Network, read our Medium Post.

Read the original Request for Applications for the Ben Barres Early Career Acceleration Awards, and for the Collaborative Science Awards.

Project Investigator

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PROJECT DETAILS

We will address the role of astrocytes in neurodegeneration. Astrocytes have been traditionally understudied relative to the role of neurons. We will investigate how astrocytes regulate neuronal synapse formation and function from development to aging, how dysfunctional astrocytes contribute to neurodegenerative disease, and how astrocytes may be used to stimulate synaptic repair in disease.


DISEASE

Alzheimer's Disease, General Neurodegeneration

SCIENTIFIC APPROACH

Cell Biology, Biochemistry

PROJECT DETAILS

Mammalian hosts are constantly exposed to gut-resident bacteria and to bacterial pathogens in the environment. It is increasingly clear that bacteria can signal to the nervous system to regulate neurophysiology, CNS inflammation, and neurodegeneration. Amyotrophic Lateral Sclerosis (ALS) is a devastating motor neuron degenerative disease with few effective treatments. In this project, we investigate the role that bacteria play in regulating neurodegeneration in ALS. Our major goals in this project are to: a) Determine whether the gut microbiome alters inflammation, neuronal loss, and disease progression in ALS mice; b) Determine whether bacterial infections trigger neurodegeneration; and c) Engineer a specific bacterial toxin to deliver pro-survival factors into motor neurons to treat ALS. Utilizing bacterial manipulation or engineering their toxins to modulate neurotoxicity could be transformative approaches to treat devastating motor neuron diseases.


DISEASE

ALS/FTD

SCIENTIFIC APPROACH

Immunology, Microbiology, Cell Biology

PROJECT DETAILS

We will apply single-cell technology to human brain samples with Alzheimer's disease to investigate the contributions of distinct cell types to disease pathogenesis and identify the transcriptome changes associated with tau pathology. We will extend this work to other neurodegenerative tauopathies with the goals of uncovering the shared and distinct transcriptome alterations in tauopathies and define the molecular signatures of tau-mediated neurodegeneration. We will focus in preclinical and early-stage disease to identify the earliest, potentially upstream mechanisms; generate multi-omics data; and validate findings in brain tissue. Further comparisons between human samples and mouse models of disease will be pursued to identify evolutionary conserved mechanisms. Our overall goal is to provide improved frameworks for the study of neurodegenerative tauopathies by generating unbiased, comprehensive, and validated single-cell data from clinically relevant human tissue.


DISEASE

Alzheimer's Disease, General Neurodegeneration

SCIENTIFIC APPROACH

Neuropathology, Single-Cell Profiling

PROJECT DETAILS

Neurodegeneration research has mainly focused on the brain and the compromised neurons and circuits. Nevertheless, evidence points to roles for body-to-brain connections (via peripheral nervous system and/or a compromised blood-brain-barrier, BBB) and inflammation mediated by non-neuronal brain cells. We plan to focus on (1) understanding the role of the periphery in propagating neurodegeneration; and (2) engineering non-invasive gene-delivery tools that specifically target non-neuronal brain cells relevant to neurodegeneration, such as immune cells and brain endothelial cells comprising the vasculature, since an impaired BBB can initiate and/or precipitate neurodegeneration. We will also contribute methods that enable the biodistribution of systemically delivered molecules (such as whole-body tissue-clearing and labeling) to aid understanding and prevention of neurodegeneration.


DISEASE

General Neurodegeneration

SCIENTIFIC APPROACH

Molecular Biology, Virology, Cell Biology

PROJECT DETAILS

A common feature across many neurodegenerative disorders is that they are caused by the expansion of nucleotide-repeat sequences in DNA that leads to RNA products that induce cellular toxicity. Despite the central importance of these toxic RNA products in neurodegeneration, we still do not know the mechanism by which these RNAs or their associated hallmarks lead to neurodegeneration. In this proposal, we will make use of our expertise in RNA biology and experience developing innovative new tools for studying RNA biology, RNA-protein interactions, and RNA-mediated bodies in the nucleus to decipher the molecular components of these mutant RNA foci; determine how these RNA-protein aggregates assemble upon disease progression; and understand how they impact global mRNA processing within neurons. Using these approaches, we will explore known repeat-containing RNAs that are genetically linked to neurodegenerative disorders to understand common features of RNA-induced toxicity in neurons.


DISEASE

ALS/FTD

SCIENTIFIC APPROACH

RNA Biology, Cell Biology, Molecular Biology

PROJECT DETAILS

Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease that causes complete paralysis and eventual death from the rapid and progressive loss of motor neurons. While a number of inherited mutations have been identified as causing ALS, the vast majority of patients have no known causal mutation or family history of disease. My lab has recently partnered with the NYGC ALS Consortium to undertake a large-scale integrated analysis of molecular alterations in ALS patients. The scale of this dataset allowed for a clean separation of ALS patients into a small set of distinct subtypes. One of these ALS subtypes involves the reactivation of endogenous retrotransposons, viral-like genomic parasites that normally lay dormant in the genome. This proposed study will develop novel machine learning software to systematically identify the genetic factors and molecular mechanisms that lead to motor neuron cell death, with a particular focus on retrotransposon reactivation.


DISEASE

ALS/FTD

SCIENTIFIC APPROACH

Genomics, Computational Biology

PROJECT DETAILS

The gut microbiome is increasingly implicated in neurodegenerative diseases, with links to amyloid pathology, microglial activation, neurodegeneration, motor impairments and cognitive decline in animal models. However, molecular and cellular mechanisms underlying how the gut microbiota influences core symptoms of neurodegenerative disease remain undefined. To address these gaps, my lab will investigate how genetic and environmental risk factors for neurodegeneration modify the gut microbiome, and how interactions between the gut microbiome and immune and nervous systems contribute to disease initiation and progression. The goal is to develop an integrated framework for interactions between the brain and periphery over time, toward identifying early mediators and biomarkers for neurodegenerative disease.


DISEASE

General Neurodegeneration

SCIENTIFIC APPROACH

Immunology, Microbiology, Cell Biology

PROJECT DETAILS

While immune cells have been implicated in pathogenesis of neurodegenerative diseases, we know relatively little about T-cell composition, their antigen specificity or functional status in these disorders. Dr. Jiang will leverage systems immunology tools that her lab developed to profile single T-cells that infiltrate into the brain during neurodegeneration. These experiments will be informative for understanding the role of the immune system in neurodegeneration and for developing immune-based detection and treatment approaches.


DISEASE

General Neurodegeneration

SCIENTIFIC APPROACH

Immunology, Genomics

PROJECT DETAILS

Our research combines systems biology with mechanistic biochemistry and cell biology to elucidate mechanisms of neurodegenerative diseases. To investigate these mechanisms in the relevant human cell types, we have developed a CRISPR-based functional genomics platform in iPSC-derived neurons and glia. To reveal cellular mechanisms underlying disease-associated genes, we use genetic modifier screens in patient-iPSC derived neurons and glia. Differentiation of iPSCs into vulnerable and resilient types of neurons makes it possible to identify causal determinants of selective vulnerability to neurodegeneration. Cell-type specific gene perturbation in neuron/glia co-culture and brain organoids enables us to dissect non-cell autonomous mechanisms of neurodegeneration. We integrate our mechanistic experiments in cell-based models with the molecular characterization of patient brain tissue at single-cell resolution.


DISEASE

General Neurodegeneration

SCIENTIFIC APPROACH

Genomics, Cell Biology, Molecular Biology, Stem Cells

PROJECT DETAILS

Large-scale chemical screening against prion-like proteins in human cells is a powerful way to discover and understand therapeutic candidates for neurodegenerative diseases. However, the ways that new compounds work and the routes to advance them to the clinic are unclear. This is challenging because we must combine large cellular screen datasets, tangled webs of drug-target interactions, and a diverse array of possible neurodegenerative mechanisms into actionable information. Drug-target binding informs therapeutic compound development from the bottom up, and cellular screening does so from the top down: where they meet, each meaningfully constrains the solutions of the other. Consequently, we will determine the biological mechanisms of promising new drug-like compounds using interpretable deep learning, to improve understanding of proteinopathies and accelerate drug discovery for neurodegenerative diseases.


DISEASE

General Neurodegeneratione

SCIENTIFIC APPROACH

Structural Biology, Computational Biology

PROJECT DETAILS

The blood-brain barrier (BBB) is a dynamic endothelial interface that separates the bloodstream from the brain, and it contains many transporter proteins that maintain homeostasis by shuttling biomolecules between each compartment. Deregulation of BBB transporter expression is observed in many neurodegenerative diseases, and BBB transporters can either enhance or hinder drug permeation into the brain depending on their relative expression and activity. However, the molecular cues and signaling networks that influence these transporters are poorly understood, making it difficult to determine how transporters are naturally regulated and subsequently altered by disease. The focus of this project is to use cell engineering strategies to systematically deconstruct mechanisms that govern BBB transporter expression and regulation. Our overall goal is to better understand how BBB dysfunction impacts neurodegeneration, which may inform future treatment strategies.


DISEASE

General Neurodegeneration

SCIENTIFIC APPROACH

Stem Cells, Cell Biology, Molecular Biology

PROJECT DETAILS

Our scientific goal is twofold. First, we want to understand the pathogenic mechanisms of mutant proteins in neurodegeneration. Second, we aim to test the hypothesis that neurodegenerative diseases can be instigated or accelerated by dysfunction of the innate immune system. Our study has an important therapeutic implication, as its findings may provide a rationale for targeting the innate immune system to decelerate or even eradicate neurodegenerative diseases.


DISEASE

General Neurodegeneration

SCIENTIFIC APPROACH

Immunology, Cell Biology

PROJECT DETAILS

There is a major opportunity to use computational biology to accelerate discovery across neurodegenerative disease research. While extraordinary technological progress has revealed large numbers of genes and pathways associated with neurodegeneration, to get at the mechanisms that explain pathogenesis and identify therapeutic innovations requires many labor-intensive experiments. In my lab, we develop novel statistical methods, employing probabilistic modeling and machine learning to find patterns in genomic data that allow us to discover the 3D protein interactions, RNA complexes, and — most critically for neurodegenerative disease pathophysiology — their dynamics, alternative conformations, and propensity to form structures that may progress to fibrils. We are excited to collaborate and bring together research from clinicians, molecular biologists, and geneticists to build tools to transform our ability to address these devastating processes.


DISEASE

General Neurodegeneration

SCIENTIFIC APPROACH

Computational Biology

PROJECT DETAILS

A growing body of evidence indicates that obesity in mid-life increases the risk of dementia later in life, and that interventions that reduce obesity can be neuroprotective. We will test if improvements in metabolic state can slow or delay neurodegeneration in mice. To identify cellular and molecular level shared between metabolic and neurodegenerative disease, we will use 3D cultures of human pluripotent stem cell-derived neurons, astrocytes, and microglial cells to test how dietary factors and hormones promote neuronal loss.


DISEASE

Alzheimer's Disease, Parkinson's Disease, General Neurodegeneration

SCIENTIFIC APPROACH

Metabolism, Stem Cells, Cell Biology

PROJECT DETAILS

We propose to leverage technology we developed in the lab to build self-organizing 3D human cellular systems that capture neural-glial interactions and inter-regional neural cross-talk. We will use this powerful preparation, also known as brain assembloids, to uncover the programs underlying prolonged maturation of neurons and astrocytes in humans and model specific genetic forms of neurodegenerative disorders. This work could lead to novel strategies and tools for modeling brain maturation and neurodegeneration with patient-derived cells and could ultimately bring therapeutic insights.


DISEASE

General Neurodegeneration

SCIENTIFIC APPROACH

Stem Cells, Cell Biology

PROJECT DETAILS

Synaptic and neuronal dysfunction is a characteristic early feature of neurodegenerative disorders, and usually predates neuronal death. Central to synaptic maintenance are intercellular signaling mechanisms that mediate synaptic homeostasis. We recently discovered that the neuronal gene Arc, a master regulator of synaptic plasticity and memory, also has a fundamental role in a novel form of intercellular communication that resembles retrovirus biology.


DISEASE

Alzheimer's Disease

SCIENTIFIC APPROACH

Cell Biology, Molecular Biology

PROJECT DETAILS

Many neurodegenerative diseases exhibit intracellular “traffic jams,” or disrupted transport of proteins and RNA. However, we know little about how transport machinery chooses its cargoes. Our work seeks to elucidate rules for how cargoes are chosen, for example, which RNAs and proteins are carried by which motor proteins. The composition of intracellular cargoes is often disrupted in a subset of neurodegenerative diseases caused by expansions in repetitive DNA sequences, such as Huntington's Disease, Myotonic Dystrophy, and Amyotrophic Lateral Sclerosis (ALS). While mouse models have provided insights into disease pathogenesis, repetitive sequences in mice do not expand quickly enough to model human disease over decades. Therefore, we propose to accelerate repeat expansion to better model neurodegenerative processes. In summary, both efforts — elucidation of how cargoes are trafficked, and acceleration of repeat expansion in vivo — will provide important insights into neurodegeneration.


DISEASE

Repeat expansion disorders including ALS/FTD, Huntington's disease

SCIENTIFIC APPROACH

RNA Biology, Cell Biology

Lead Project Investigator

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TEAM MEMBERS

Ernest Arenas, MD, PhD

Karolinska Institutet (Lead PI)

Per Svenningsson, MD, PhD

Karolinska Institutet (Clinical PI)

Sten Linnarsson, PhD

Karolinska Institutet

Mats Nilsson, PhD

Stockholm University


PROJECT DETAILS

Parkinson’s disease (PD) is an incurable progressive neurodegenerative disorder that affects a growing proportion of the aging population, and its cause is largely unknown. We propose to gain insights into the molecular mechanisms of PD. Our objectives are: 1) Identify alterations in gene expression at a single cell level in PD samples by using powerful droplet microfluidics single-nuclei RNA-seq, single molecule FISH, in situ sequencing and bioinformatics analysis; and 2) Determine the function of genes with altered expression levels and their contribution to PD by using novel gene editing technologies and advanced midbrain differentiation protocols for pluripotent stem cells. Our project will systematically analyze and provide an unbiased understanding of the cell types and molecular mechanisms involved in PD. This will enable us to define molecular pathways, disease subtypes, markers and possible targets for future therapeutic intervention.


DISEASE

Parkinson's Disease

SCIENTIFIC APPROACH

Single-Cell Profiling, Stem Cells, Computational Biology


TEAM MEMBERS

Marc Diamond, MD

UT Southwestern Medical Center (Lead PI)

Charles White, MD

UT Southwestern Medical Center (Clinical PI)

Lukasz Joachimiak, PhD

UT Southwestern Medical Center


PROJECT DETAILS

Neurodegenerative diseases such as Alzheimer’s are based on accumulation of the tau protein and have myriad presentations. It is critical to understand the basis of this variability to achieve precise diagnosis and treatment, but current methods of neuropathology are not adequate to explain why patients experience different types of disease. Tau has many characteristics similar to the prion protein, including the formation of distinct, highly ordered assemblies (also termed “strains”) that have unique 3D structures, determining the nature of pathology they cause in the brain. This project combines structural biology, biochemistry, and neuropathology in an attempt to precisely link novel tau structures with specific diseases. It will develop new tools to analyze tau from human brain tissues, with the goal of achieving more precise diagnosis based on quantitative measures. This could enable more personalized approaches to the diagnosis and treatment of neurodegenerative diseases.


DISEASE

Alzheimer's Disease, FTD

SCIENTIFIC APPROACH

Structural Biology, Cell Biology, Biochemistry


TEAM MEMBERS

Cagla Eroglu, PhD

Duke University (Lead PI)

Nicole Calakos, MD, PhD

Duke University (Clinical PI)

Albert La Spada, MD, PhD

Duke University


PROJECT DETAILS

Parkinson's disease (PD) is a neurodegenerative movement disorder caused by the death of dopaminergic neurons. Mutations in several genes cause familial forms of PD, but how these mutations trigger neurodegeneration is still largely unknown. Studies on these genes have been mostly restricted to neurons; however, some PD-linked genes are also highly expressed by non-neuronal brain cells called astrocytes. We will test the functions of PD genes in astrocytes as controllers of neuronal health and connectivity by applying novel molecular tools to manipulate these genes in both primary rodent and patient cell-derived astrocyte-neuron cultures and in transgenic mice, and utilize cell biological and physiological readouts of astrocyte-synapse signaling, synaptic connectivity, and neuronal health. We expect to identify new functions for PD-genes specifically in astrocytes and elucidate how astrocytes dysfunction could mediate neuron loss.


DISEASE

Parkinson's Disease

SCIENTIFIC APPROACH

Cell Biology, Biochemistry


TEAM MEMBERS

Philip L. De Jager, MD, PhD

Columbia University (Lead and Clinical PI)

Elizabeth Bradshaw, PhD

Columbia University

Vilas Menon, PhD

Columbia University

Vladislav Petyuk, PhD

Senior Scientist, Pacific Northwest National Laboratory


PROJECT DETAILS

Recent convergent work has put a spotlight on microglial cells in the brain as a key part of the brain’s immune response in a broad range of neurodegenerative diseases. The field has lacked robust and reliable tools for dissecting the role of these cells, especially in human samples. To address this gap, this team will generate key reference data and a microglia experimental toolkit to identify and target different human microglial subtypes, with plans to make these tools available to the broader research community.


DISEASE

Alzheimer's Disease, General Neurodegeneration

SCIENTIFIC APPROACH

Neuropathology, Single-Cell Profiling, Stem Cells, Computational Biology


TEAM MEMBERS

Celeste Karch, PhD

Washington University in St. Louis (Lead PI)

Gregory Day, MD

Washington University in St. Louis (Clinical PI)

Carlos Cruchaga, PhD

Washington University in St. Louis

Oscar Harari, PhD

Washington University in St. Louis


PROJECT DETAILS

The goal of this project is to apply a novel, systems biology approach that leverages multi-omics in stem cells and human tissues to elucidate the mechanisms by which common genetic drivers of neuroinflammation confer resilience to neurodegenerative disease. Rare variants in the gene TREM2 are associated with a significantly increased risk of Alzheimer’s, Parkinson’s, and frontotemporal lobar degeneration. Our proposal focuses on the gene MS4A4A, which we have identified as a new regulator of TREM2 that may contribute to AD resilience. If successful, the project could lead to a deeper mechanistic understanding of the pathological mechanisms by which TREM2, MS4A4A contribute to disease and to the identification of candidate biomarkers and therapeutic targets.


DISEASE

Alzheimer's Disease

SCIENTIFIC APPROACH

Molecular Biology, Cell Biology, Stem Cells, Single-Cell Profiling


TEAM MEMBERS

William Seeley, MD, PhD

University of California, San Francisco (Lead and Clinical PI)

Steven Altschuler, PhD

University of California, San Francisco

Aimee Kao MD, PhD

University of California, San Francisco

Lani Wu, PhD

University of California, San Francisco


PROJECT DETAILS

Our team is trying to transform how we study the pathophysiological links between genetic risk pathways and molecular pathology. We seek to build a new discovery platform by studying linked in vitro models and post-mortem tissues from the same individual patients. We will use high-dimensional histologic and transcriptomic profiling, analyzed through innovative machine learning-based methods, to identify shared phenotypes within each paired system and across methods and patients. Candidate mechanistic pathways that emerge will have high disease-relevance and robustness due to the human-based and methodologically convergent nature of the strategy. Those candidate mechanisms will then flow naturally into human cell models for perturbation and treatment-related experiments. If successful, this work could begin to provide a new approach for identifying, validating, and pursuing potential therapeutic targets for neurodegenerative disease.


DISEASE

ALS, General Neurodegeneration

SCIENTIFIC APPROACH

Neuropathology, Single-Cell Profiling, Stem Cells, Computational Biology


TEAM MEMBERS

Patrik Verstreken, PhD

VIB-KU Leuven (Lead PI)

Wim Vandenberghe, MD, PhD

KU Leuven (Clinical PI)

Dries Braeken, PhD

imec Leuven


PROJECT DETAILS

There currently are no drugs that slow down or stop the progression of Parkinson’s disease. The key limitation to understanding and treating neurodegenerative disorders such as Parkinson’s is the lack of disease models that reproduce all clinically relevant aspects of these diseases. Therefore, we will develop the technology to produce mature human neuronal microcircuits relevant to Parkinson’s disease on a multi-electrode array chip. Using the chip’s built-in recording circuitry, we will be able to compare the induced neuronal circuits of cells obtained from healthy people and from an extensive collection of Parkinson patients. This unique platform will allow us to test the role of pathogenic pathways on neuronal network dysfunction and screen for novel therapeutic approaches.


DISEASE

Parkinson's Disease

SCIENTIFIC APPROACH

Stem Cells, Nanoengineering, Molecular Biology


TEAM MEMBERS

David Walt, PhD

Harvard University (Lead PI)

Alice-Chen Plotkin, MD

University of Pennsylvania (Clinical PI)

George Church, MD

Harvard University


PROJECT DETAILS

Presently, it is impossible to measure biomarkers in the blood that can detect Parkinson’s Disease early and monitor its progression. Our goal is to isolate tiny nanoscale-sized packets from the blood containing the contents of brain cells. These packets are called extracellular vesicles (EVs). Our goal is to capture EVs released specifically from brain neurons, so we can “read out” their RNA and protein profiles and apply them to study the course of neurodegenerative diseases in patients. To accomplish this goal, we will develop methods to isolate brain-specific EVs using unbiased computational and experimental techniques. We will develop robust isolation techniques to capture EVs based on specific surface protein markers. After isolation, we will use a new ultrasensitive protein measurement technology and high-throughput RNA sequencing to characterize the contents of these EVs. These methods can transform our current understanding of the course and progression of neurodegeneration.


DISEASE

Parkinson's Disease

SCIENTIFIC APPROACH

Cell Biology, Single-Cell Profiling, Biochemistry


TEAM MEMBERS

Gene Yeo, PhD

University of California, San Diego (Lead PI)

Jeffrey D. Rothstein, MD, PhD

Johns Hopkins University (Clinical PI)


PROJECT DETAILS

Alterations in nucleocytoplasmic transport (NCT) have emerged as a prominent pathomechanism underlying multiple neurodegenerative diseases. However, the precise mechanism by which NCT is disrupted in neurodegeneration remains largely unknown. We will use iPSC technology and a combination of molecular, biochemical, and imaging approaches to determine cell type specific alterations in and the effect of ALS/FTD associated mutations on nuclear pores.


DISEASE

ALS/FTD

SCIENTIFIC APPROACH

Cell Biology, Single-Cell Profiling, Stem Cells