Spinal muscular atrophy (SMA) represents the most common genetic cause of infant mortality. This autosomal recessive neuromuscular disorder is characterized by degeneration of the anterior horn cells of the spinal cord, leading to symmetrical muscle weakness and atrophy. The pathomechanism is still unclear and currently there is no cure or treatment available to stop its progression. SMA is caused by mutations or deletions in the ubiquitously expressed gene encoding the survival of motor neuron protein (SMN). Previous work has focused mainly on the essential role of SMN in the efficient assembly and remodeling of spliceosomal ribonucleoprotein (RNP) complexes in all cell types. It is still unknown why motor neurons are so specifically vulnerable to low levels of SMN and how SMN deficiency selectively causes motor neuron cell death. In neurons, SMN is found located in both the nucleus and in neurites and it is actively transported in the form of dynamic granules. This suggests a novel neuron-specific function of SMN and we hypothesize that an inefficiency of axonal SMN-associated RNPs may contribute to SMA. To better understand the biological role of SMN in the development and maintenance of motor axons, we propose to investigate the in vivo localization of SMN-RNP complexes. We will generate transgenic mice that express biological functional Smn fused to a fluorescent protein reporter to study the dynamic localization of Smn-containing RNP granules during development. Previously, we have shown that growth cones and distal axons of SMN deficient primary motor neurons contain reduced levels of ?- actin mRNA and protein. New data suggest that Smn-deficiency affects transport and/or local translation of additional transcripts and we will identify and study these affected transcripts and proteins. This proposal will focus on a novel approach to overcome limitations of primary cell culture by using stem-cell derived motor neurons growing as compartmentalized cultures that separate cell bodies and axons. We will identify RNAs that are transported in axons of wild type and SMN-deficient motor neurons and we will also compare the proteome of locally translated proteins in the axons of wild type and Smn-deficient motor neurons. Our results will clarify a potential role of SMN in the transport, stability or local translation of mRNAs in neuronal processes. As these processes have been linked to growth cone motility and axon guidance, it is of big interest to find out how SMN may be involved and how defects in the delivery of RNP complexes may trigger or at least modulate the disease process in SMA. The proposed research is also important more broadly for understanding the function of mRNA localization during the development of the nervous system. Spinal muscular Atrophy (SMA) is an inherited pediatric disease caused by mutations or deletions in a gene encoding the survival motor neuron protein (SMN) that results in rapid degeneration of spinal cord motor neurons and is the leading genetic cause of infant mortality. Its pathomechanism is still unclear and currently there is no cure or treatment available to stop its progression. We propose studies on the axonal function of SMN and the underlying molecular pathology of SMA that have the potential to reveal essential aspects of motor neuron function and development and also to suggest therapeutic strategies for this disease. ? ?
| Rossoll, Wilfried; Bassell, Gary J (2009) Spinal muscular atrophy and a model for survival of motor neuron protein function in axonal ribonucleoprotein complexes. Results Probl Cell Differ 48:289-326 |
