Pathogenesis of proximal autosomal recessive spinal muscular atrophy

Scientific paper - Review paper

• Author: Goran Šimić
• Author's institution: University of Zagreb; School of Medicine
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Clinical Medical Sciences

Abstract (english)

Although it is known that deletions or mutations of the SMN1 gene on chromosome 5 cause decreased levels of the SMN protein in subjects with proximal autosomal recessive spinal muscular atrophy (SMA), the exact sequence of pathological events leading to selective motoneuron cell death is not fully understood yet. In this review, new findings regarding the dual cellular role of the SMN protein (translocation of β-actin to axonal growth cones and snRNP biogenesis/pre-mRNA splicing) were... More integrated with recent data obtained by detailed neuropathological examination of SMA and control subjects. A presumptive series of 10 pathogenetic events for SMA is proposed as follows: (1) deletions or mutations of the SMN1 gene, (2) increased SMN mRNA decay and reduction in full-length functional SMN protein, (3) impaired motoneuron axonoand dendrogenesis, (4) failure of motoneurons to form synapses with corticospinal fibers from upper motoneurons, (5) abnormal motoneuron migration towards ventral spinal roots, (6) inappropriate persistence of motoneuron apoptosis due to impaired differentiation and motoneuron displacement, (7) substantial numbers of motoneurons continuing to migrate abnormally (“heterotopic motoneurons”) and entering into the ventral roots, (8) attracted glial cells following these heterotopic motoneurons, which form the glial bundles of ventral roots, (9) impaired axonal transport of actin, causing remaining motoneurons to become chromatolytic, and (10) eventual death of all apoptotic, heterotopic and chromatolytic neurons, with apoptosis being more rapid and predominating in the earlier stages, with death of heterotopic and chromatolytic neurons occurring more slowly by necrosis during the later stages of SMA. According to this model, the motoneuron axonopathy is more important for pathogenesis than the ubiquitous nuclear splicing deficit. It is also supposed that individually variable levels of SMN protein, together with influences of other phenotype modifier genes and their products, cause the clinical SMA spectrum through differential degree of motoneuron functional loss. Less

• Keywords (english): Apoptosis; Chromosomes, Human, Pair 5/genetics; Cyclic AMP Response Element-Binding Protein/genetics; Genes, Recessive; Humans; Motor Neurons/pathology; Mutation; Nerve Tissue Proteins/genetics; RNA-Binding Proteins/genetics; SMN Complex Proteins; Spinal Muscular Atrophies of Childhood/etiology; Spinal Muscular Atrophies of Childhood/genetics; Spinal Muscular Atrophies of Childhood/pathology; Survival of Motor Neuron 1 Protein
• Language: english
• Publication type: Scientific paper - Review paper
• Publication status: Published
• Peer review: Peer review
• Publication version: Accepted version
• Journal title: Acta neuropathologica
• Numbering: vol. 116, no. 3, pp. 223-234
• p-ISSN: 0001-6322
• DOI: https://doi.org/10.1007/s00401-008-0411-1
• URN:NBN: urn:nbn:hr:105:223315
• Publication: 2008-09
• Document URL: https://doi.org/10.1007/s00401-008-0411-1
• Type of resource: Text
• Access conditions: Open access
• Created on: 2024-03-28 11:26:06