Selective loss of specific neuronal subsets is a universal feature of neurodegenerative diseases ranging, from Alzheimer's disease to Parkinson's disease. Although the nature of the disease trigger is only known for familial forms of disease, such triggers are in general expressed widely throughout the CNS. This raises a fundamental question in neurology: why do specific subsets of neurons degenerate in response to dysfunction of a ubiquitously expressed protein? Proximal spinal muscular atrophy (SMA) provides a unique opportunity to address these questions. SMA is a fatal neuromuscular disease characterized by differential loss of motor pools, anatomically discrete groups of motor neurons with a well-defined function - contraction of a single muscle in the periphery. For example, severe functional impairment of intercostal muscles in combination with functional sparing of the diaphragm produces a """"""""bell-shaped"""""""" chest that is pathognomonic of SMA. Moreover, all patients with SMA have homozygous loss of function of the survival motor neuron (SMN) gene. Mouse models with loss of SMN are therefore representative of the disease in all patients. Studying selective motor pool vulnerability in SMA may uncover principles of selective neurodegeneration that can be applied to other disorders. This project aims to identify candidate therapeutic targets by identifying intrinsic molecular differences between vulnerable and resistant motor pools. Specifically, I will isolate RNA and perform transcriptional profiling on 12 differentially affected motor pools in SMA. These motor pools have diverse physiology, presynaptic connectivity, and wide anatomic distribution along the neuraxis. Therefore, I hypothesize that differentially expressed genes and pathways are promising candidates for contributing to disease resistance. I will manipulate these candidate genes in the SMN?7 mouse model of SMA and assess for improvements in pathology, such as cell loss or neuromuscular denervation. Successful candidate genes represent promising targets for translation into human SMA and other neurodegenerative disorders that share common pathways. Future studies that focus on underlying mechanisms of neuroprotection may provide insight into principles of neurodegeneration broadly.

Public Health Relevance

Neurodegenerative diseases are among the most costly and devastating diseases in terms of financial burden and impact on human lives, with disease burden growing inexorably as the U.S. population ages. Proximal spinal muscular atrophy (SMA) is a fatal pediatric motor neuron disease uniquely suited for uncovering neurodegenerative disease mechanisms, due to its uniform genetics and easily accessible cell populations. This study aims to identify genes that contribute to disease resistance in SMA patients with the aim of identifying novel therapeutic targets for this disorder and gaining insigh into principles of neurodegeneration broadly.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30AG044989-02
Application #
8672192
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Chen, Wen G
Project Start
2013-07-01
Project End
2017-01-15
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Physical Medicine & Rehab
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10032
Iascone, Daniel M; Henderson, Christopher E; Lee, Justin C (2015) Spinal muscular atrophy: from tissue specificity to therapeutic strategies. F1000Prime Rep 7:04