The overriding theme of the Udall Center at Columbia has been to develop approaches to therapy which prevent progression of disease, and, if also possible, provide lasting restoration of neurologic function. Our efforts have two guiding principals. The first is that development of such therapies ultimately depends on a better understanding of mechanisms of disease. The second is that patients cannot wait for a full understanding of this disease to be in hand before efforts are made to translate new knowledge of mechanisms into treatments. This Project is focused on this second principal. In the current funding period, we have achieved real progress towards this goal by implementing knowledge about the regulation of cell death in the design of two novel gene therapy approaches. One of these approaches utilized dominant negative forms of the mixed lineage kinases to block apoptosis;the other used a constitutively active form of Akt (Myr-Akt). We have identified three limitations of these approaches that we now seek to overcome. First, only the AAV1 Myr-Akt approach protected the axons of the nigrostriatal projection. This feature will be essential for effective future therapies, so it must be refined and developed. Second, our evidence for neuroprotection by Myr-Akt has been obtained only in neurotoxin models;studies must be performed in models with more likely relevance to the human disease. Third, the use Myr-Akt is fraught with many possible undesirable effects, including oncogenesis. Effort must be made to identify downstream pathways that exclusively mediate the desired neuroprotection phenotype. This Project therefore has three Aims intended to address these limitations.
In Aim I, we will attempt to validate our observations that Myr-Akt protects not only neuron cell bodies, but also axons. In this Aim, we will also explore whether mTor is a mediator of axon protection, and, if so, whether it does so by suppression of autophagy.
In Aim II, we will examine whether the ability of Myr-Akt to protect axons generalizes to a new mouse model that is more likely to be relevant to human PD. We have demonstrated that the principal pathology observed in hl_RRK2(R1441G) BAG transgenic mice is an axonopathy affecting the nigrostriatal projection.
In Aim III, we will explore the possibility that the undesired oncogenic phenotype of Akt can be circumvented by the use of a closely-related, but non-oncogenic, kinase, serum and glucocorticoid-induce kinase, hSGK1. Resolution of these limitations will be important steps forward in the development of neuroprotective treatments of PD.

Public Health Relevance

Current therapies for PD treat only its symptoms, not its progression. The goal of our research is to use new knowledge about the mechanisms of neurodegeneration in PD to develop therapies that will block the ongoing neurodegeneration. We have developed one very promising gene therapy approach that uses a protein called Akt, a kinase that protects neurons and their axons from degeneration. The goal of this Project is to improve this approach and to develop promising second-generation alternatives.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
2P50NS038370-11
Application #
7664233
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2009-09-30
Budget End
2010-07-31
Support Year
11
Fiscal Year
2009
Total Cost
$337,358
Indirect Cost
Name
Columbia University (N.Y.)
Department
Type
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Guerreiro, Rita; Ross, Owen A; Kun-Rodrigues, Celia et al. (2018) Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study. Lancet Neurol 17:64-74
Sun, Xiaotian; Aimé, Pascaline; Dai, David et al. (2018) Guanabenz promotes neuronal survival via enhancement of ATF4 and parkin expression in models of Parkinson disease. Exp Neurol 303:95-107
Wu, Di; Klaw, Michelle C; Connors, Theresa et al. (2017) Combining Constitutively Active Rheb Expression and Chondroitinase Promotes Functional Axonal Regeneration after Cervical Spinal Cord Injury. Mol Ther 25:2715-2726
Kun-Rodrigues, Celia; Ross, Owen A; Orme, Tatiana et al. (2017) Analysis of C9orf72 repeat expansions in a large international cohort of dementia with Lewy bodies. Neurobiol Aging 49:214.e13-214.e15
Guerreiro, Rita; Escott-Price, Valentina; Darwent, Lee et al. (2016) Genome-wide analysis of genetic correlation in dementia with Lewy bodies, Parkinson's and Alzheimer's diseases. Neurobiol Aging 38:214.e7-214.e10
Wu, Di; Klaw, Michelle C; Kholodilov, Nikolai et al. (2016) Expressing Constitutively Active Rheb in Adult Dorsal Root Ganglion Neurons Enhances the Integration of Sensory Axons that Regenerate Across a Chondroitinase-Treated Dorsal Root Entry Zone Following Dorsal Root Crush. Front Mol Neurosci 9:49
Robakis, Daphne; Cortes, Etty; Clark, Lorraine N et al. (2016) The effect of MAPT haplotype on neocortical Lewy body pathology in Parkinson disease. J Neural Transm (Vienna) 123:583-8
Louis, Elan D; Clark, Lorraine; Ottman, Ruth (2016) Familial Aggregation and Co-Aggregation of Essential Tremor and Parkinson's Disease. Neuroepidemiology 46:31-6
Chung, Sun Young; Kishinevsky, Sarah; Mazzulli, Joseph R et al. (2016) Parkin and PINK1 Patient iPSC-Derived Midbrain Dopamine Neurons Exhibit Mitochondrial Dysfunction and ?-Synuclein Accumulation. Stem Cell Reports 7:664-677
Pereira, Daniela B; Schmitz, Yvonne; Mészáros, József et al. (2016) Fluorescent false neurotransmitter reveals functionally silent dopamine vesicle clusters in the striatum. Nat Neurosci 19:578-86

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