The major adult-onset degenerative neurological diseases, e.g., amyotrophic laterals sclerosis (ALS), Alzheimer's disease (AD), and Parkinson's disease (PD), selectively affect specific populations of neurons. These cells exhibit characteristic abnormalities of the neuronal cytoskeleton, e.g., in ALS, motor neurons show chromatolysis, perikaryal neurofilaments (NF), and neurofilamentous swellings of proximal axons. In these diseases, it has been suggested that these dysfunctional neurons also exhibit alterations in transmitter enzymes and receptors. Little is known about the mechanisms and consequences of these structural/chemical pathologies in human disease. On the basis of our animal studies, we have hypothesized that the cytoskeletal pathology may arise by a number of mechanisms, including alterations in levels of messenger RNA, changes in the character of specific proteins, impaired interactions of organelles, and alterations in axonal transport. We suggest that these dysfunctional neurons may also show alterations of transmitter markers/receptors. To explore these hypotheses, we have begun to use neurobiological approaches to investigate several animal models of cytoskeletal disorganization, e.g., axonal transection, aluminum poliomyelopathy, the axonopathy associated with intoxication with beta,beta'-iminodipropionitrile (IDPN), acrylaminde neuropathy, and Hereditary Canine Spinal Muscular Atrophy (HCSMA), an autosomal dominant disorder of motor neurons. In these models, we plan to test our hypotheses using a variety of strategies, including cDNA probes on Western blots/in situ hybridizations, polyacrylamide gel electrophoresis (PAGE)/Western blots, immunocytochemistry, freeze-fracture/deep-etch techniques, radiometric-gel fluorographic analyses, and receptor autoradiography. We plan to systematicaly explore the mechanisms underlying these experimental disorders and to apply similar strategies to investigations of cell populations at risk in ALS and other adult-onset degenerative disorders.
| Griffin, J W; Clark, A C; Parhad, I et al. (1991) The neuronal cytoskeleton in disorders of the motor neuron. Adv Neurol 56:103-13 |
