Helen & Robert Appel Alzheimer’s Disease Research Institute

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Projects

Burre Laboratory

Dysfunction of STXBP1 in infantile epileptic encephalopathies

Principal Investigator:
Dr. Jacqueline Burre

The American Epilepsy Society and The Epilepsy Foundation ( 01/01/2015 – 12/31/2015)

Mutations in STXBP1 are associated with Ohtahara syndrome, West syndrome, and Dravet syndrome. These syndromes are devastating infantile epileptic encephalopathies, characterized by progressive cerebral dysfunction, leading to cognitive, sensory and/or motor function deterioration due to unremitting epileptic activity. STXBP1 is a neuronal protein which is essential for neurotransmitter release. Since 2008, more than 30 de novo mutations have been identified in the STXBP1 gene, which are linked to these seizure disorders. Yet, the impact of mutations on STXBP1 function is unknown. The goal of this grant is to investigate how disease-linked mutations in STXBP1 affect its function in vitro.

Function and Dysfunction of Synucleins at the Synapse

Principal Investigator:
Jacqueline Burre, PhD

Leon Levy Foundation (02/01/2015 – 01/31/2016)

The interplay and contribution of α-, β- and γ-synuclein to the pathogenesis of diseases termed synucleinopathies is unknown. Synucleins are abundantly expressed in the brain, where they  localize to synaptic terminals. Yet, despite 25 years of research, their normal function remains unknown. Similarly, it remains enigmatic how synucleins trigger devastating diseases such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy, frontotemporal dementia, and Gaucher’s disease. The goal of this grant is to investigate the interplay of α-, β- and γ-synuclein with regard to their physiological functions and pathological activities.

Aging increases the aggregation-prone cytosolic pool of α-synuclein

Principal Investigator:
Dr. Jacqueline Burre

American Parkinson Disease Association (09/01/2015 – 08/31/2016)

Age is the biggest risk factor for developing Parkinson’s disease (PD), and α-synuclein pathology is a causal link to PD. In nerve terminals, α-synuclein cycles between a membrane-bound pool on synaptic vesicles and a cytosolic pool, and we have previously found that membrane-binding of α-synuclein protects it from aggregation. Yet, our understanding of age-dependent dynamics in intracellular α-synuclein pools is poor. The goal of this grant is to determine age-dependent changes in the subcellular localization of α-synuclein that lead to α-synuclein aggregation and pathology, and to identify triggers for this altered localization.
 

A small molecule approach to rescuing protein misfolding in infantile epileptic encephalopathies

Principal Investigator:
Jacqueline Burre, PhD

Sanofi Innovations Awards Program, Sanofi (12/20/2016-12/19/2017)

The goal of this grant is to reverse the specific dysfunctions caused by mutant STXBP1 using a small molecule approach.

Molecular mechanisms of Munc18-1 linked infantile seizure disorders and rational rescue strategies.

Principal Investigator:
Jacqueline Burre, PhD

NIH/NINDS (3/1/2017-2/28/2022)

The goal of this grant is to identify the disease mechanism underlying Munc18-1 linked infantile epilepsies, and to develop rescue strategies to combat pathogenic events.

Paul Laboratory

The role of Hsp90 in Alzheimer’s disease

Principal Investigator:
Wenjie Luo, PhD

National Institutes of Health/National Institute on Aging Grant

The overall objective is to provide new therapeutic strategies for AD treatment. Based on our preliminary data, our studies demonstrate that Hsp90 binds to mutant APP and regulates its metabolism. Therefore, we hypothesize that Hsp90 is critical in dysregulated APP processing and modulates the progression of AD.  We characterize the regulatory roles of Hsp90 in amyloid generation by investigating the dynamic Hsp90-APP interaction and its impact on APP processing/trafficking. Then finally, the therapeutic effects of Hsp90 inhibitors will be determined in a mouse model of AD.

Genomic analysis of bipolar disorder in a genetic isolate (NIH/NIMH R01 Grant)

Principal Investigator:
Steven Paul, MD

National Institutes of Health/National Institute of Mental Health Grant

To identify and fully elaborate genetic variants that underlie the susceptibility to develop a highly heritable form of mental illness, bipolar affective disorder in a well-studied and phenotyped genetic isolate, the Old Order Amish.

Treatments for Alzheimer’s disease

Principal Investigator:
Steven Paul, MD

Johnson & Johnson Pharmaceuticals

To discover a human or humanized anti-tau monoclonal antibody which recognizes a pathological tau conformation (s) and readily blocks the propagation of misfolded tau protein in vivo and the resulting neurodegeneration and disease progression which characterizes Alzheimer’s disease (AD).

Apolipoprotein E biology in Alzheimer's disease

Principal Investigator:
Steven Paul, MD

AstraZeneca Pharmaceuticals

To advance our fundamental knowledge of the role apoE plays in the etiology and pathogenesis of AD, i.e. in order to delineate one or more novel drug targets for potentially treating and (or) preventing AD.

Gene delivery of apolipoprotein E2 as a treatment for Alzheimer's disease

Principal Investigator:
Steven Paul, MD

Alzheimer’s Drug Discovery Foundation (ADDF)

To quantify the effects of apoE2 expression on brain Aβ/amyloid burden by comparing the effects of both intracerebral as well as intraventricular gene delivery of apoE2 using two viral vectors (AAV2 and lentivirus) on apoE2 expression and brain amyloid burden in the PDAPP mouse model of Alzheimer’s disease. 

In this project we extended our earlier studies on apoE2 gene delivery as a potential treatment strategy for AD by using an optimized and well-studied viral vector(s) and exploring relatively non-invasive routes of CNS administration. Specifically, we will explore the utility of the Rhesus serotype adeno-associated viral vector (AAVrh.10) and two different delivery approaches or routes of administration (e.g. direct intracerebral/intraparenchymal and intracisternal) in mice (using a new and more relevant transgenic AD mouse model) to facilitate an eventual clinical trial of apoE2 gene delivery in AD patients.

Investigating the role of microglia in tau clearance in Alzheimer's disease

Principal Investigator:
Dr. Wenjie Luo

Coins for Alzheimer's Research Trust (CART)

This project focuses on characterization of the cellular pathways and regulatory mechanisms involved in tau clearance by microglia. The data generated from this study will help address several fundamental questions regarding tau clearance by microglia and will provide novel therapeutic interventions for treating Alzheimer's disease by targeting a microglial-mediated tau clearance pathway.

Petsko Laboratory

Stabilization of alpha-synuclein as therapeutic strategy for Parkinson's disease

Principal Investigator:
Gregory A. Petsko, D. Phil.

The Michael J. Fox Foundation for Parkinson’s Research Grant

The overall objective of this grant is to complete the NMR structure determination of a new, tetrameric form of alpha-synuclein discovered in this lab and repeat the structure determination for one or more of the Parkinson’s Disease-associated mutants of the protein.  It is further proposed to verify that this form exists in neurons and that the ratio of this form to that of the fibrilar form of the protein changes with the inset and progression of Parkinson’s Disease, thereby validating stabilization of the tetramer as a novel approach to the prevention of the disease, and to develop inhibitors to block the proteolytic processing of the protein.

Mechanisms of Enzymic Proton and Hydride Transfers

Principal Investigator:
Dr. Gregory A. Petsko

National Institutes of Health/National Institute of General Medicinal Sciences Grant

The overall objective of this project is to use time-resolved and other forms of protein crystallography to achieve an understanding of the structural basis for efficient enzymic catalysis of hydrogen transfer from weakly acidic carbon and oxygen centers. 

High Throughput Screening for Compounds to Mitigate Toxicity of FUS/TLS & SOD1

Principal Investigator:
Dr. Gregory A. Petsko

National Institutes of Health

The goal of this project is to identify compounds that suppress the toxicity fo fUS/TLS to motor neurons, and to find small molecules that either stabilize the dimeric form of superoxide dismutase or lower its expression in the central nervous system.

The Role of FUS/TLS in Familial Amytrophic Lateral Sclerosis by Studies in a Model Organism

Principal Investigator:
Dr. Gregory A. Petsko

ATA - The ALS Therapeutic Alliance

The overall objective of this proposal is to develop a system in a model organism that permits genetic and biochemical studies of the role of the protein FUS/TLS in the neurologic disease ALS, and to exploit that system both for such studies and as a vehicle for high-throughput screening for drugs that may ameliorate FUS/TLS-induced cytotoxicity.  In parallel, studies of the structure of FUS/TLS will be carried out with the aim of using in silico screening to find drugs that will stabilize the nuclear-bound form of the protein.

New Approaches to the Prevention and Treatment of Neurologic Disorders

Principal Investigator:
Dr. Gregory A. Petsko

Fidelity Biosciences Research Initiative (FBRI)

The overall objective is to identify, functionally characterize, and exploit new targets for the prevention and treatment of several neurologic disorders, with emphasis on Alzheimer’s, Parkinson’s and Lou Gehrig’s diseases.

Effect of APOE on CNS Neurons: Role of LRP

Principal Investigator:
Gregory A. Petsko, D. Phil.

National Institute of Neurological Disorders & Stroke (NINDS)

This research project is aimed at investigating several aspects of the "disease biology" of Alzheimer's disease (AD) with an overall goal of developing disease-modifying therapies to treat or prevent AD. This is accomplished by using a variety of transgenic mouse models of AD pathology shown to have apoE isoform-dependent effects on brain amyloid deposition/burden (apoE4>apoE3>>apoe2) in aging mutant APP transgenic mice. This approach closely recapitulates what is observed in humans who have high genetic risk (apoE4 carriers) for AD (measured by PET imaging).

Novel gene therapy modality increasing retromer expression

Principal Investigator:
Gregory A. Petsko, D. Phil.

Meira GTx (12/5/2016-12/4/2019)

The main goal of this project is to identify ALL of the genes that regulate retromer function in mammalian cells, not just at the level of transcription, but also in terms of mRNA stability, translation control, protein half-lives, and biochemical function.

Investigating genes that suppress the proteotoxicity of FUS/TLS and TDP-43

Principal Investigator:
Gregory A. Petsko, D. Phil.

Meira GTx (7/7/2015-7/6/2017)

We propose a focused program to investigate the scope of hUPF1 and hUPF2-mediated suppression of ALS-related protein cytotoxicity, with an emphasis on establishing the mechanism by which it works and identifying additional suppressor genes.

Gene therapeutic modulation of NMD for treatment of ALS

Principal Investigator:
Gregory A. Petsko, D. Phil.

Target ALS Foundation (1/1/2017-12/31/2017)

The goals of this project is to confirm the efficacy of NMD modulation in ALS model animals and to find the optimum form of either hUPF1 or hUPF2 for gene therapy use in the human disease.The ideal construct would have maximal therapeutic efficacy at doses nowhere near any toxic level. For this purpose, we propose to create three new variants of both proteins: catalytically dead, more stable, and with improved NMD function.

Sharma Laboratory

Tau Proteostasis by Hsc70 Co-Chaperones

Principal Investigator:
Dr. Manu Sharma

American Federation for Aging Research (AFAR) New Investigator Award in Alzheimer's Disease

Microtubules are tiny tubular structures in cells that act like conveyor belts, moving vesicles, granules, chromosomes, and organelles such as mitochondria via special attachment proteins. Tau protein molecules stabilize these microtubules. But when tau proteins become defective, pathologies of the nervous system (such as Alzheimer’s disease) can develop. Defective tau proteins accumulate in the form of aggregates in the neurons of Alzheimer’s disease patients and consequently lead to neuron loss and cognitive decline. The objective of Dr. Sharma’s research is to achieve a better understanding of the molecular machinery that suppresses tau aggregation in neurons. Dr. Sharma and his group will use biochemical, cell biological, and whole-animal approaches to investigate how Hsj1 (a co-chaperone protein) causes tau degradation, thus possibly reducing tau aggregation and pathology. They expect their research to give them a clear understanding, in molecular detail, of how Hsj1 acts to reduce tau in neurons. They also expect to clarify whether this action of Hsj1 protects against neurodegeneration driven by tau aggregation. Dr. Sharma’s research, if successful, could make a huge impact on the treatment of Alzheimer’s disease by informing therapeutic strategies that mimic or boost the activity of cellular tau-degrading mechanisms.

Tau Proteostasis by Cysteine String Protein-alpha (CSP-alpha)

Principal Investigator:
Dr. Manu Sharma

Alzheimer’s Association New Investigator Research Grant (NIRG)

Aggregation of microtubule-associated protein tau is a hallmark of age-dependent neurodegeneration in Alzheimer’s disease and other tauopathies. While tau mutations are strongly associated with some tauopathies (e.g. frontotemporal dementia), the vast majority of cases with tauopathic neurodegeneration do not result from tau mutations: for example, no tau mutation is known to cause Alzheimer’s disease. Thus, there is a critical need to understand why wild type tau fails to retain its native conformation, and forms pathogenic oligomers and aggregates. Our objective here is to delineate the molecular mechanism of tau proteostasis, and how this mechanism modifies tau aggregation and neurodegeneration. Based upon our preliminary data in combination with published studies, our central hypothesis is that tau aggregation and neurodegeneration are reduced by three proteostatic mechanisms: via structural stabilization by the CSPα/Hsc70 “foladase” complex, via turnover by the CHIP/Hsc70 “degradase” complex, and/or via disaggregation by the Hsp110/Hsc70 complex. At the completion of our studies, we expect to have (i) determined in molecular detail, how CSPα stabilizes tau and affects tau aggregation, (ii) included this novel activity in the overall context of tau proteostasis: which of CSPα, CHIP and/or Hsp110 is most effective at reducing tau aggregates while maintaining native tau, and (iii) determined in vivo how these proteostatic mechanisms protect against tau-driven neurodegeneration.

DnaJ co-chaperones which modify tau aggregation and neurodegeneration in Alzheimer's disease

Principal Investigator:
Manu Sharma, PhD

NIH/NIA (8/1/2016-5/31/2021)

The central goal of this project is to understand whether and how tau aggregation and neurodegeneration are affected by the activities of two neuronal chaperone machines: CSPα/Hsc70/SGT-foldase, which stabilizes tau and the Hsj1/Hsc70/CHIP-degradase which turns over tau.

Cellular mechanism of Adult Onset Neuronal Ceroid Lipofuscinosis (ANCL) caused by mutations in cysteine string protein-alpha (CSPalpha)

Principal Investigator:
Manu Sharma, PhD

NIH/NINDS (4/1/2017-3/31/2022)

The central goal of this project is to understand how mutations in synaptic chaperone CSPα, which cause Adult onset neuronal ceroid lipofuscinosis (ANCL), disrupt the function of CSPα in stabilizing the SNARE-protein SNAP-23; and how destabilization of SNAP-23 disrupts lysosomal pathology of ANCL. We also propose to rescue these defects using specific chemical chaperones.

Proteostasis by Hsc70 Co-Chaperones CHIP and Hsj1

Principal Investigator:
Manu Sharma, PhD

American Federation for Aging Research (AFAR) New Investigator Award in AD (7/1/2015-6/30/2017)

The central goal of this project is to understand how the co-chaperones CHIP and Hsj1 affect tau degradation and pathological aggregation in neurons. An additional goal of this New Investigator Award is to encourage new PIs to generate data toward getting longer term funding.

Tau Proteostasis by Tau Proteostasis by Cysteine String Protein-alpha (CSPα)

Principal Investigator:
Manu Sharma, PhD

Alzheimer's Association New Investigator Research Grant (10/1/2015-9/30/2017)

The central goal of this project is to understand how the synaptic co-chaperone protein CSPα affects the stability and aggregation of tau in neurons. An additional goal of this New Investigator Award is to encourage new PIs to generate data toward getting longer term funding.

 

Weill Cornell Medicine Helen & Robert Appel Alzheimer’s Disease Research Institute 413 East 69th Street New York, NY 10021 Phone: (646) 962-6323 Fax: (646) 962-0579