Diss. (sammanfattning) Umeå : Univ., 2004. / Härtill 4 uppsatser.

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Amyotrophic lateral sclerosis and spinal muscular atrophy are the two most common motoneuron diseases. Both are characterized by destabilization of axon terminals, axon degeneration and alterations in neuronal cytoskeleton. Accumulation of neurofilaments has been observed in several neurodegenerative diseases but the mechanisms how elevated neurofilament levels destabilize axons are unknown so far. Here, I show that increased neurofilament expression in motor nerves of pmn mutant mice causes disturbed microtubule dynamics. Depletion of neurofilament by Nefl knockout increases the number and regrowth of microtubules in pmn mutant motoneurons and restores axon elongation. This effect is mediated by interaction of neurofilament with the stathmin complex. Depletion of neurofilament increases stathmin-Stat3 interaction and stabilizes the microtubules. Consequently, the axonal maintenance is improved and the pmn mutant mice survive longer. We propose that this mechanism could also be relevant for other neurodegenerative diseases in which neurofilament accumulation is a prominent feature. Next, using Smn-/-;SMN2 mouse as a model, the molecular mechanism behind synapse loss in SMA is studied. SMA is characterized by degeneration of lower α-motoneurons in spinal cord; however, how reduction of ubiquitously expressed SMN leads to MN-specific degeneration remains unclear. SMN is involved in pre-mRNA splicing (Pellizzoni, Kataoka et al. 1998) and its deficiency in SMA affects the splicing machinery. Neuromuscular junction denervation precedes neurodegeneration in SMA. However, there is no evidence of a link between aberrant splicing of transcripts downstream of Smn and reduced presynaptic axon excitability observed in SMA. In this study, we observed that expression and splicing of Nrxn2, that encodes a presynaptic protein is affected in the SMA mouse and that Nrxn2 could be a candidate that relates aberrant splicing to synaptic motoneuron defects in SMA. / Die Amyotrophe Lateralsklerose und die spinale Muskelatrophie sind die beiden häufigsten Formen der Motoneuronerkrankungen. Sie sind charakterisiert durch eine Destabilisierung der Axonendigungen, durch Axondegeneration und durch Änderungen im neuronalen Zytoskelett. Eine Anhäufung von Neurofilamenten konnte in einigen neurodegenerativen Erkrankungen beobachtet werden. Der genaue Mechanismus, welcher zu einer Destabilisierung des Axons führt, ist bis heute jedoch unklar. Hiermit zeige ich, dass eine gesteigerte Expression von Neurofilamenten in motorischen Nerven von pmn mutierten Mäusen zu einer Störung der Mikrotubuli – Dynamik führt. Ein Neurofilamentabbau durch Nefl knockout steigert die Anzahl an neu wachsenden Mikrotubuli in pmn mutierten Motoneuronen und führt zu erneutem Axonwachstum. Dieser Effekt wird durch eine Interaktion zwischen dem Neurofilament und dem Stathmin Komplex vermittelt. Ein Abbau des Neurofilaments führt zu einer Erhöhung der Stathmin-Stat3 Interaktion und zu einer Stabilisierung der Mikrotubuli. Demzufolge ist die Versorgung der Axone verbessert und die pmn mutierten Mäuse überleben länger. Wir vermuten, dass dieser Mechanismus auch für andere neurodegenerative Erkrankungen, bei denen Neurofilamentanhäufung ein dominantes Merkmal ist, relevant sein könnte. Des Weiteren studierte ich mit Hilfe des Smn-/-;SMN2 Mausmodels, den molekularen Mechanismus der sich hinter dem Synapsenverlust bei SMA verbirgt. SMA ist charakterisiert durch eine Degeneration der unteren -Motoneuronen im Rückenmark. Es ist jedoch unklar, wie ein Verlust des ubiquitär exprimierten SMN Proteins zu einer MN-spezifischen Degeneration führt. Smn ist involviert in den Prozess des pre-mRNA Splicing (Pellizzoni, Kataoka et al. 1998) und ein Verlust des Proteins führt zu einer Störung des Splicing. Eine Denervierung der motorischen Endplatte führt zu einer Neurodegeneration in SMA. Es gibt jedoch keinen Hinweis auf eine kausale Verbindung zwischen anomalem Splicen von stromabwärts gelegenen Transkripten des Smn und einer Reduktion präsynaptischer Axone, wie man es bei SMA beobachten kann. In dieser Studie konnten wir beobachten, dass Expression und Splicing von Nrxn2, welches für ein präsynaptisches Protein kodiert, in SMA Mäusen betroffen ist und dass Nrxn2 ein Kandidat sein könnte, der eine Verbindung zwischen Störungen im Splice Prozess und synaptischen Motoneuron-Defekten in der SMA herstellen könnte.

Indiana University-Purdue University Indianapolis (IUPUI) / A histological marker of Parkinson’s disease (PD) is the loss of synapses located on striatal medium spiny neurons (MSNs) as a result of dopaminergic nigral cell depletion. The dendritic spines that give MSNs their name have a well-characterized structure and are the main regions of post-synaptic input. It has been shown that spines have altered functionality and morphology in many neurodegenerative diseases. Spine morphology, and potentially function, is dictated by an array of structural proteins and their associations with other proteins in a region dubbed the post-synaptic density (PSD). Spinophilin and neurofilament medium (NF-M) are two proteins that are enriched in the PSD and have potential implications in PD. Interestingly, preliminary data show that there is a decrease in the NF-M-spinophilin interaction in animal models of PD. Here it is shown that these two proteins interact in brain tissue and when overexpressed in a mammalian cell system. Moreover, we have begun to determine mechanisms that regulate this interaction. It is known that there is a misregulation of protein phosphatases and kinases in many neurodegenerative diseases. Moreover, the phosphorylation state of a protein can regulate its association with other proteins. Therefore, we hypothesize that the phosphorylation state of either protein affects the interaction between spinophilin and NF-M. Furthermore, we have conducted experiments utilizing protein phosphatases and kinases that are known to modulate the phosphorylation state of NF-M and/or spinophilin. Data show that both kinase and phosphatase activity and/or expression modulates the NF-M-spinophilin interaction in heterologous cell lines. Through the use of MS/MS analysis, we have begun to map specific phosphorylation sites that may play a role in regulating this interaction. Currently, we are elucidating the specific effects of these post-translational modifications on regulating the spinophilin-NF-M interaction. These data will enhance our knowledge of spinophilin’s interactions and how these interactions are altered in neurological disorders such as PD.

Multiple sclerosis is chronic, autoimmune and neurodegenerative disorder of central nervous system. Currently, we have only limited markers of disease activity. From clinical markers, speech markers were analysed. Data from 141 patients and 70 healthy controls were evaluated. The most important results were detection of speech abnormalities in patients with minimal neurological disability (EDSS<2) and their correlations with global and regional brain atrophy. This work is predominantly concetrated on neurofilament light chain (NfL) as one of the most promising paraclinical biomarkers. NfL, especially level of serum NfL (sNfL), is considered to be a biomarker of future disease course, disease activity and effect of DMD (disease modifying drugs) therapy. The main aim was to clarify the position of NfL among others biomarkes and their potential benefit for routine clinical praxis. MRI data, clinical data and results of NfL measurements from 172 newly diagnosed patients with relaps-remiting MS (revised McDonald criteria 2017) from original SET cohort were analysed. Additionally, we compared levels of serum and CSF NfL with other biochemical parameters, such as lipidogram and markers of blood-brain permeability. We found sNfL as a marker of ongoing neuroinflammation and predictor of future brain atrophy...

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Thesis (Ph. D.)--Case Western Reserve University, 2005. / [School of Medicine] Department of Pathology. Includes bibliographical references. Available online via OhioLINK's ETD Center.

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