Intracellular transport is fundamental for neuronal function and survival. The majority of proteins are synthesized in the neuron cell body and transported along axons and dendrites through molecular motors as the Kinesin superfamily proteins (KIFs). Two specific KIFs that have been associated strongly with neurodegenerative processes in humans and in rodents are KIF5A and KIF21B. In fact, KIF5A down regulation has been associated with axonal transport defects in models of multiple sclerosis (MS) and a genome wide association screen for MS correlated single nucleotide polymorphisms located in the KIF21B intron with the disease, establishing this kinesin as a susceptibility locus for MS. Since nitric oxide (NO) has a key role in mediating inflammatory axonopathy in MS promoting protein mis-folding, disruption of mitochondrial respiratory chain and organelle fragmentation, the first aim of the present study was to determine the effect of NO exposure on the expression of KIF5A and KIF21B in rodent cortical neurons and to evaluate whether KIFs expression correlates with axon pathology. Results demonstrated that NO cause a time dependent decrease of gene and protein expression for both KIF proteins. Furthermore, dot blot analysis showed that NO cause a time dependent decrease in axon phosphorylation and that KIFs reduction precede the loss of neurofilament. Human bone marrow mesenchymal stem cells (MSCs) represent a promising candidate for neuronal repair due to anti-inflammatory, antioxidant and neurotrophic properties. The second part of this study was therefore to investigate the capacity of MSC to protect neurons and axonal transport mechanisms in rodent cortical neurons exposed to NO. Results showed that MSC were able to preserve axonal length and increase survival in cortical neurons exposed to NO, furthermore MSCs had the ability to preserve both KIF5A and KIF21B protein expression from nitric oxide damage. Finally in this study, it was evaluated if there were any changes in KIFs gene and protein expression in cerebellum of MS patients in relation to appropriate control patients. Results demonstrated significant changes in KIF5A and KIF21B expression and the presence of KIF positive spheroids aggregates in sections derived from MS patients. In conclusion, the results of this study allow a better understanding of the mechanisms involved in the abnormal accumulation of proteins in axons during oxidative insult, that represent a hallmark of several neurodegenerative disorders. Moreover, the ability of MSCs to protect KIF expression from NO damage provides further evidence of their significant therapeutic potential in multiple sclerosis.
(2012). Role of kinesin superfamily proteins in neurodegeneration. (Tesi di dottorato, Università degli Studi di Milano-Bicocca, 2012).
|Data di pubblicazione:||13-dic-2012|
|Titolo:||Role of kinesin superfamily proteins in neurodegeneration|
|Settore Scientifico Disciplinare:||BIO/16 - ANATOMIA UMANA|
|Corso di dottorato:||NEUROSCIENZE - 17R|
|Citazione:||(2012). Role of kinesin superfamily proteins in neurodegeneration. (Tesi di dottorato, Università degli Studi di Milano-Bicocca, 2012).|
|Parole Chiave (Inglese):||Axonal transport; kinesin superfamily proteins; multiple sclerosis; nitric oxide; mesenchymal stem cells|
|Appare nelle tipologie:||07 - Tesi di dottorato Bicocca post 2009|