Role of Growth Factors and Apoptosis Proteins in Cognitive Disorder Development in Patients with Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease; it occurs due to a mutation in the dystrophin protein gene; as a result, the protein is not synthesized and muscle tissue dies. On the one hand, we can say that this disease has been sufficiently studied; however, it is still incurable, and there are a number of issues remaining unclear in terms of the development of progressive dementia as a symptom in 30% of patients with Duchenne muscular dystrophy. We conducted a study at the intersection of molecular genetic, neurological, and enzyme-linked immunosorbent patients’ blood tests and experiments in organotypic culture, which allowed us to determine important points in the development of cognitive disorders in patients with Duchenne muscular dystrophy and identify a significant effect of growth factor concentration in patients. The chapter will present data on neurotrophic regulation in patients with Duchenne muscular dystrophy (by the best-studied neurotrophins), demonstrate special aspects of neuron-myocyte interaction, and broaden the understanding of the role of apoptosis and synthase proteins in the development of this disease. We would like to highlight the importance of prognostic criteria for the development of cognitive impairment and possible therapeutic measures to prevent progressive dementia

Differential Neurotrophic Regulation of Sodium and Calcium Channels in an Adult Sympathetic Neuron

Adult neuronal phenotype is maintained, at least in part, by the sensitivity of individual neurons to a specific selection of neurotrophic factors and the availability of such factors in the neurons' environment. Nerve growth factor (NGF) increases the functional expression of Na+ channel currents ( INa) and both N- and L-type Ca2+ currents ( ICa,N and ICa,L) in adult bullfrog sympathetic ganglion (BFSG) B-neurons. The effects of NGF on ICa involve the mitogen-activated protein kinase (MAPK) pathway. Prolonged exposure to the ganglionic neurotransmitter luteinizing hormone releasing hormone (LHRH) also increases ICa,N but the transduction mechanism remains to be elucidated as does the transduction mechanism for NGF regulation of Na+ channels. We therefore exposed cultured BFSG B-neurons to chicken II LHRH (0.45 μM; 6–9 days) or to NGF (200 ng/ml; 9–10 days) and used whole cell recording, immunoblot analysis, and ras or rap-1 pulldown assays to study effects of various inhibitors and activators of transduction pathways. We found that 1) LHRH signals via ras-MAPK to increase ICa,N, 2) this effect is mediated via protein kinase C-β (PKC-β-ΙΙ), 3) protein kinase A (PKA) is necessary but not sufficient to effect transduction, 4) NGF signals via phosphatidylinositol 3-kinase (PI3K) to increase INa, and 5) long-term exposure to LHRH fails to affect INa. Thus downstream signaling from LHRH has access to the ras-MAPK pathway but not to the PI3K pathway. This allows for differential retrograde and anterograde neurotrophic regulation of sodium and calcium channels in an adult sympathetic neuron.