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The pathogenesis of spinal muscular atrophy in humans is based on an innappropriate persistence of normally occurring motor neuron apoptosis


Šimić, Goran; Šešo-Šimić, Đurđica
The pathogenesis of spinal muscular atrophy in humans is based on an innappropriate persistence of normally occurring motor neuron apoptosis // Proceedings of 6th Multinational Congress on Microscopy / Milat, O ; Ježek, D (ur.).
Zagreb: Croatian Society for Electron Microscopy, 2003. str. 283-283 (poster, domaća recenzija, sažetak, znanstveni)


Naslov
The pathogenesis of spinal muscular atrophy in humans is based on an innappropriate persistence of normally occurring motor neuron apoptosis

Autori
Šimić, Goran ; Šešo-Šimić, Đurđica

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
Proceedings of 6th Multinational Congress on Microscopy / Milat, O ; Ježek, D - Zagreb : Croatian Society for Electron Microscopy, 2003, 283-283

Skup
6th Multinational Congress on Microscopy

Mjesto i datum
Pula, Hrvatska, 01-05.06.2003

Vrsta sudjelovanja
Poster

Vrsta recenzije
Domaća recenzija

Ključne riječi
Apoptosis; cell death; electron-microscopy; spinal muscular atrophy

Sažetak
Spinal muscular atrophy (SMA) is the second most common autosomal recessive disease (after cystic fibrosis) and the second most common neuromuscular disease (after muscular dystrophy). We used electron-microscopical (EM) analysis as well as TUNEL and ISEL methods to assess DNA fragmentation, and immunocytochemistry to identify expression of the apoptosis-related proteins bcl-2 and p53 in postmortem spinal cords of children with clinical diagnosis of SMA. The diagnosis was confirmed by mutation analysis of exons 7 and 8 of SMN and exon 5 of NAIP gene using PCR. Control subjects did not suffer from any neurological abnormality. EM analysis in the tissue from children with SMA revealed neurons with clearly apoptotic morphology (type 1 according to Clarke): condensation of the nucleus and cytoplasm, margination of condensed chromatin, blebbing of nucleus and plasma membrane, segregation and disintegration of the nucleus. These features of cell death could not be found in controls. Occasionally, degenerating neurons with a combination of type 1 and type 2 cell death (autophagic degeneration) were found in SMA children as well. In contrast to controls, who were virtually free of any TUNEL or ISEL-positive cells, in all children with SMA both TUNEL and ISEL revealed a substantial number of anterior horn motor neurons (which is in line with the known time kinetics of apoptosis), as well as microglial cells, that displayed positivity for fragmented DNA. The intact nucleus of TUNEL-positive microglial cells suggested that these cells have indeed phagocytosed dying apoptotic neurons rather than that they are undergoing apoptosis themselves. Bcl-2 immunocytochemistry showed a pronounced loss of cytoplasmic expression in remaining motor neurons of SMA subjects, while nuclear expression of p53 protein was much stronger in SMA than in controls. In conclusion, our results indicate that an absent or decreased anti-apoptotic activity of SMN and NAIP underlies the inappropriate persistence of normally occurring motor neuron programmed cell death after 25th week of gestation. This is clear not only from TUNEL-and ISEL-positive motor neurons but also from ultrastructurally confirmed apoptotic morphology, which was absent in controls. The apoptotic mechanism of cell death was further supported by the prominent phagocytosis of fragmented DNA by solitary microglial cells. The occurrence of apoptosis as a possibly predominant mechanism of neuronal death in SMA is important with respect to future strategies directed towards a cytoprotective therapy of SMA. Estimated kinetics, immunocytochemical and EM features of cell death found in SMA were compared with those known for Alzheimer's disease where DNA fragmentation indicates only increased neuronal vulnerability, but not apoptosis.

Izvorni jezik
Engleski

Znanstvena područja
Kliničke medicinske znanosti



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Projekt / tema
0108258