Investigation of molecular and genetic controls over survival and degeneration of sub-type specific neuron populations in relation to disease is critically important. Neurodegenerative diseases stem from progressive and cell-type specific degeneration of a defined neuron population in the CNS. Today, the cellular and molecular mechanisms of cell-type specific degeneration are poorly understood. It is not clear why in the complex structure of the brain only specific neuron populations undergo cell death. Our limited understanding of cell-type specificity not only hinders finding approaches for cure, but also restricts our ability to early detect the vulnerability of a defined neuron population. We are coming to realize that the cortex cannot be defined only by layers, but must also be defined by sub-type specific neuron populations that are molecularly related to each other. The genetic make-up of different projection neurons and inter-neurons are beginning to emerge (Fishell, 2007; Molyneaux et al., 2007). Using pure populations of sub-type specific neurons, the molecular controls over their birth and specification, as well as their neuronal maturation and axon outgrowth are identified (Arlotta et al., 2005; Ozdinler and Macklis, 2006).

Corticospinal motor neurons (CSMN) reside in layer V of motor cortex, and together with spinal motor neurons progressively degenerate in amyotrophic lateral sclerosis (ALS). CSMN degeneration is also observed in primary lateral sclerosis and hereditary spastic paraplegia. In addition, CSMN degeneration contributes to the long-term paralysis in spinal cord injury. Callosal projection neurons (CPN) are born together with CSMN, reside together with CSMN in layer V, but they are not affected in such diseases. Sub-type specific neurons share common biology, common molecular structure, and during times of disease they share a common destiny. This common, yet undefined molecular signature could be one major reason why a defined neuron population is more vulnerable in a disease.

Symptoms of motor neuron degeneration develop late into disease progression; however, cell death starts much earlier. This indicates the presence of an intrinsic molecular mechanism that makes these neurons more vulnerable to disease. Understanding the molecular and genetic controls over CSMN specific vulnerability can offer a tool to identify the basis of cell-type specific degeneration of this clinically relevant neuron population. Investigation of pure populations of CSMN isolated from well-defined animal models of diseases at two critical time points, and using CPN as a control neuron population will allow identification of key genes/cluster of genes or molecular pathways which may reflect in human disease pathology. Our findings will help to identify novel molecular markers that can be used for early diagnosis, and may enhance development of effective therapies in the future.

Other Grants

Lindsay M. De Biase, Ph.D., University of California Los Angeles
The role of microglial lysosomes in selective neuronal vulnerability
Synapses, the sites of signaling between neurons in the brain, play essential roles in learning, memory, and the health of neurons themselves. An enduring mystery is why some neurons are…
How the nervous system constructs internal models of the external world
As animals navigate their environments, they construct internal models of the external sensory world and use these models to guide their behavior. This ability to incorporate ongoing sensory stimuli into…
Xiaojing Gao, Ph.D., Stanford University
When Neural Circuits Meet Molecular Circuits: Quantitative Genetic Manipulation with Single-cell Consistency
Cells are the building blocks of our bodies. We get sick when the cells “misbehave”. The way modern gene therapies work is to introduce genes, fragments of DNA molecules that…
Rafiq Huda, Ph.D., Rutgers University
Conducting the orchestra of movement—functional role of striatal astrocytes in health and disease
Movement requires coordinated activity across a large brain-wide network. The striatum is a particularly important part of this circuit; it integrates motor-related information from many distinct brain regions to regulate…