Naslov
Pathogenesis of spinal muscular atrophy

Autori
Šimić, Goran

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

Skup
Neuroscience Summer School, RIKEN Brain Science Institute

Mjesto i datum
Tokyo, Japan, 26.07.2002

Vrsta sudjelovanja
Predavanje

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
spinal muscular atrophy type I (Werdnig-Hoffmann disease ; Guido Werdnig ; Johann Hoffmann ; SMN gene ; SMN protein ; spliceosome ; splicing ; spinal cord ; anterior horns' motoneurons ; glial bundles ; neuropathology

Sažetak
Guido Werdnig was the first who reported two cases of the infantile progressive familial form of spinal muscular atrophy (SMA) in 1891. After acquiring his M.D., Werdnig served in the Austro-Hungarian army for a decade in South Dalmatia and Bosnia, which were at that times Austrian crown land, as Bosnia was occupied by Austro-Hungarian troops in 1878. In this period Werdnig published articles in a military journal on the problems of wounded soldiers. In 1888 Werdnig, now a civilian, moved to Graz where he worked as a neurologist and became associated with the Institute of Pathological Anatomy. He returned to Vienna in 1896 and resumed neurological practice. Unfortunately, Werdnig's discovery was not acknowledged or prized during his lifetime. Due to stroke, he became paraplegic and was bedridden for 12 years before he died totally forgotten in a public sanatorium. Werdnig’s brilliantly described SMA neuropathological features: the loss of anterior horns' neurons, 2. empty cell "beds", 3. glial cell bundles in the ventral spinal roots, 4. heterotopic motoneurons. Independently of Werdnig, Johann Hoffmann also described chronic familiar SMA in 1889. Johann Hoffmann was educated at Worms and graduated medicine at Heidelberg. As an assistant in the Dept. of Neurology he worked with professor Wilhelm Erb (1840-1921) whom he later replaced as the head. Late in life he was appointed as full professor of neuropathology. His name is part of at least five important eponyms in medicine: 1) Hoffmann's reflex – finger reflex due to hyper-reflexia, 2) Hoffmann's phenomenon – excessive irritability of the sensory nerves due to electrical or mechanical stimuli in tetany, 3) Hoffmann's sign – an electrophysiological sign of tetany, 4) Hoffmann's syndrome – a muscular symptom complex associated with acquired hypothyreosis, and last but not least 5) Werdnig-Hoffmann disease. This type of SMA is now called SMA-1. Although clinically classified as types 0 (diminished fetal movements in utero and presenting at birth with asphyxia and severe weakness), I, II, III and IV, the spectrum of the disease is quite continuous. The intercostal muscles are always affected, whereas the diaphragm is usually spared, allowing adequate spontaneous respiratory activity until the infants are precipitated into respiratory failure by an incidental respiratory infection, or aspiration. Only humans are having 2 SMN genes, all other species are having one, so its mutation is embryonically lethal. Different copy number of the SMN2 gene is thought to occur by random duplication events. However, in a small population of SMA patients, the SMN1 gene is converted to the SMN2 gene by replacing exons 7 and 8 (gene conversion). In SMA-2 and SMA-3 missense point mutations are also far more common than in SMA-1 type. Amount of full-length (functional) SMN protein correlates with the SMA severity. Approximately 23% of the normal SMN protein levels are needed needed for normal motoneuron function. In other words, levels below this value cause symptoms of SMA. SMN protein is highly conserved and each of its domains is functionally important. It is found in nucleus and cytoplasm of all cells but most abundantly in alpha-motoneurons. Within the nucleus, the SMN protein forms heteromeric complexes. These SMN complexes play an important role in biogenesis of small nuclear ribonucleoproteins (snRNPs), which are important for pre-mRNA processing (splicing). SMN protein is also a component of the nuclear domains called Cajal bodies (CBs) that contain coiled threads of the marker protein (coilin). SMN protein seems to be essential for both the assembly and delivery of snRNPs to the CBs. CBs are involved in the biogenesis and recycling of splicing snRNPs, snoRNPs (nucleolar) and 3 eukaryoticRNA polymerases. However, since CBs are deficient in DNA, nascent premRNA, and non-snRNP essential splicing factors, they are probably not active sites for transcription or splicing. In SMA, low SMN protein levels result in altered CBs composition and a notable separation of SMN protein into distinct nuclear bodies called Gems (“gemini of Cajal bodies”) ; in severe cases of SMA, a dramatic reduction in nuclear gems can be observed. Otherwise, Gems and CBs mostly colocalize in some cell lines and adult tissues but are separated in fetal tissues - this indicates that Gems and Cajal bodies (as well as ICGs) are distinct nuclear structures that have a dynamic functional relationship. With a false discovery rate (FDR) set at less than 0.1, 259 genes from spinal cord, 73 from brain, and 633 from kidney were identified as having splicing pattern changes. Since only a large degree of SMN decrease (>80%) is required to cause a significant change in the levels of snRNAs or cause cell death in cultured cells, this suggests that cells normally contain a large excess capacity of SMN complex to maintain their normal inventory of snRNAs. Therefore, most experts in the field think that splicing deficit hypothesis can not adequately answer the question of selective motoneuron cell death in SMA. SMN protein has an enormous number of interactions with other proteins, but in the last several years the role of SMN protein in the control of actin dynamics has been documented as probably the most important for motoneuron survival. The first suggestion that SMN protein might have other important functions than snRNP assembly came from EM analysis of mouse spinal cord that revealed SMN protein present in dendrites and axons (Pagliardini et al. 2000). Actually, further studies confirmed that SMN accumulates in growth cone and filopodia in both neuronal- and glial-like cells ; since SMN was present at the leading edge of neurite outgrowths, this suggests its specific role in axono- and dendrogenesis (Fan and Simard, 2002). So, it is possible that the axonal-SMN isoform will be found to be selectively expressed only in developing spinal cord motoneurons. Additionally, in-situ hybridization analysis using anti-sense probe against actin mRNA in PC12 cells and motoneurons confirmed that SMN protein (Smn in mouse) colocalizes with hnRNP-R (protein that transports RNA along axons) in cell bodies and neurite-like proceses.

Izvorni jezik
Engleski

Znanstvena područja
Biologija, Temeljne medicinske znanosti, Kliničke medicinske znanosti, Kognitivna znanost (prirodne, tehničke, biomedicina i zdravstvo, društvene i humanističke znanosti)

POVEZANOST RADA