Sacsin, which is mutated in the neurodegenerative disease Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS), is a 520 kDa modular protein with regions of homology to molecular chaperones and domains linking to the ubiquitin proteasome system. This suggests a role in proteostasis. Previously, sacsin has been shown to partially localise with mitochondria, and loss of sacsin results in elongated and dysfunctional mitochondria. Moreover, alterations in neurofilaments have recently been reported in a mouse model of ARSACS. Despite these findings, pathophysiological mechanisms of ARSACS are poorly understood. The aim of this thesis was to elucidate the cellular role of sacsin by determining how loss of its function leads to the observed mitochondrial and intermediate filament defects. This hoped to shed light on the mechanism of disease in ARSACS. The results indicate that the mitochondrial elongation seen in ARSACS is likely due to reduced mitochondrial localisation of the essential fission factor DRP1. This may be mediated by loss of function of a complex involving sacsin and dynactin-6, a subunit of the dynein-dynactin motor complex, which has previously been shown to be required for DRP1 mitochondrial recruitment. DRP1-mediated mitochondrial fission is necessary for mitochondrial quality control; hence a disruption to mitochondrial quality control is likely to occur in sacsin deficient cells, which may explain the mitochondrial dysfunction in ARSACS. Furthermore, sacsin null cells display a dramatic collapse and perinuclear bundling of the vimentin intermediate filament network. This is coupled with the displacement of cellular organelles, particularly mitochondria, early endosomes and the Golgi, which accumulate at the periphery of the vimentin bundle. These are characteristic features of aggresome formation, indicating an aggregation of misfolded protein, which occurs due to disrupted proteostasis. Further supporting this, the proteostasis components ubiquitin, HSP70, LAMP2 and p62 are recruited to the perinuclear vimentin bundles. In summary, the findings of this thesis indicate a role for sacsin in mitochondrial and protein quality control, the dysfunction of which is likely to be particularly detrimental in neurons. Mitochondrial dysfunction along with protein misfolding and aggregation are implicated in many neurodegenerative diseases, and ARSACS is no exception.

A doença de Parkinson é a doença motora neurodegenerativa mais comum do mundo. Agregados proteicos contendo principalmente alfa-sinucleína é a principal marca da doença. Recentemente, tem sido demonstrado que defeitos na dinâmica mitocondrial e da autofagia são causados pelo acúmulo da proteína. No nosso estudo, foram utilizados neurônios derivados de SH-SY5Y ou de hiPSC de pacientes com a doença de Parkinson hereditária, além de leveduras para analisar a dinâmica mitocondrial e da autofagia e o envolvimento de proteínas desses processos na toxicidade da alfa- sinucleína. Foi observado a diminuição do tráfego mitocondrial em neurônios derivados das células SH-SY5Y que expressavam alfa-sinucleína A53T. Além disso a proteína mutante ainda levou ao aumento de espécies reativas de oxigênio, perturbação da autofagia e aumento da sinalização apoptótica. Os neurônios então foram tratados com NAP, um peptídeo neuroprotetor, que preveniu os efeitos tóxicos da alfa-sinucleína mutante. Leveduras contendo deleções nos genes Gem (Miro), Ypt53 (Rab5) e Atg8 (LC3) e expressando alfa-sinucleína dos tipos A30P e A53T, demonstraram que a toxicidade da alfa-sinucleína é dependente das disfunções na mitocôndria e na autofagia. A agregação da alfa-sinucleína A53T foi prevenida na ausência de Gem. Além disso, a toxicidade da proteína envolvendo a disfunção mitocondrial e sinalização apoptótica causada pelo estresse do ER foi dependente dos genes Gem e Atg8, respectivamente. Neurônios derivados de hiPSC de pacientes contendo a triplicação do gene da alfa-sinucleína, mostraram diminuição do transporte de mitocôndrias e do potencial de membrana da mitocôndria. Análises sobre a quantidade de vesículas lisossomais desses neurônios, demonstraram acúmulos dessas vesículas, sugerindo que a autofagia está alterada. Em um ensaio sobre a sensibilidade dos neurônios dopaminérgicos, foi observado que os neurônios contendo a alpha-sinucleína mutante são mais susceptíveis à rotenona, quando comparado com os neurônios dopaminérgicos do controle. A exposição à rotenona também causou mudanças na distribuição de mitocôndrias, sugerindo que o tráfego retrógrado da organela está alterado / Parkinson\'s disease (PD) is the most common motor neurodegenerative disease in the world. Protein aggregates containing mainly alpha-synuclein are a hallmark of disease. Mitochondria and autophagy defects have been suggested to be caused by alpha-synuclein toxicity. In this study, we investigated mitochondria and autophagy dynamics related to alpha-synuclein toxicity in neurons derived form SH-SY5Y cells, hiPSC from patients with familial PD or yeast. We found that SH-SY5Y neuroblastoma cells expressing A53T alfa- synuclein showed significantly inhibited mitochondrial trafficking. A53T alfa- synuclein also caused the highest increase in ROS production in the dysmobilized mitochondria in comparison to wild-type or A30P alfa- synuclein. Treatment with NAP, the 8 amino acid peptide identified as the active component of activity dependent neuroprotective protein (ADNP), completely annihilated the adverse effects of A53T on mitochondrial dynamics. During disruption of retrograde transport, we found disturbed autophagy and increased apoptosis signalization in neurons expressing A53T alpha-synuclein, suggest activation of the apoptosis pathway. Curiously, all groups expressing alpha-synuclein showed decreased levels of BCL-XL, revealing that mitochondria are susceptible to changes in the membrane potential in the presence of alphasynuclein. Nevertheless, treatment with NAP was effective in blocking the apoptosis pathway and restore autophagy. We created a model to study A30P and A53T alpha-synuclein toxicity related to Gem (Miro), Ypt53 (Rab5) and Atg8 (LC3) genes in Saccharomyces cerevisiae in which these genes were knocked down. We found that A30P alpha-synuclein toxicity was dependent on mitochondrial and autophagy dysfunction. A53T alpha-synuclein was more toxic than A30P alpha-synuclein, and its aggregation was dependent on Gem expression. A53T alpha-synuclein toxicity involving damaged mitochondrial and apoptotic signaling caused by ER stress was dependent on Gem and Atg8 genes, respectively. In a study involving dopaminergic neurons derived from hiPSCs from patients containing triplicated alpha-synuclein gene (SNCA3), we reported decreased mitochondrial trafficking and mitochondrial membrane potential, besides accumulation of lysosome vesicles. In a sensitivity assay, SNCA3 neurons demonstrated more susceptibility to rotenone toxicity, which alters intracellular mitochondrial distribution, impairing retrograde transport of the organelle

<p> <p>&nbsp / </p> </p> <p align="left">This study utilized large-scale gene expression data to define the regulatory networks of genes expressing in the hippocampus to which multiple disease pathologies may be associated. Specific aims were: ident i fy key regulatory transcription factors (TFs) responsible for observed gene expression patterns, reconstruct transcription regulatory networks, and prioritize likely TFs responsible for anatomically restricted gene expression. Most of the analysis was restricted to the CA3 sub-region of Ammon&rsquo / s horn within the hippocampus. We identified 155 core genes expressing throughout the CA3 sub-region and predicted corresponding TF binding site (TFBS) distributions. Our analysis shows plausible transcription regulatory networks for twelve clusters of co-expressed genes. We demonstrate the validity of the predictions by re-clustering genes based on TFBS distributions and found that genes tend to be correctly assigned to groups of previously identified co-expressing genes with sensitivity of 67.74% and positive predictive value of 100%. Taken together, this study represents one of the first to merge anatomical architecture, expression profiles and transcription regulatory potential on such a large scale in hippocampal sub-anatomy.</p>

<p>Cells thrive on sustaining order and balance to maintain proper homeostatic functions. However, the primary machinery involved in protein quality control including chaperones, ubiquitin proteasome system, and autophagy all decline in function and expression with age. Failures in protein quality control lead to enhanced protein misfolding and aggregation. Efficient elimination of misfolded proteins by the proteasome system is critical for cellular proteostasis. However, inadequate proteasome capacity can lead to aberrant aggregation of misfolded proteins and inclusion body formation, which is a hallmark of numerous neurodegenerative diseases. Due to the post-mitotic nature of neurons, they are more susceptible to the collapse in proteostasis correlated with age. </p><p> </p><p>Here, we propose a cell based model of aggresome clearance using a reversible proteasome inhibitor, MG132, to identify the precise molecular machinery involved in proper processing of inclusions. It is known that once misfolded proteins are aggregated, the proteasome system can no longer degrade them. Furthermore, the continuous accumulation of aggregates often leads to aggresome formation, which results in amalgamated inclusion bodies that are simply too large for autophagosomes to engulf and degrade. Although, studies have shown that aggresomes can eventually be cleared by autophagy, the molecular mechanisms underlying this process remain unclear. </p><p>Our research reveals that regardless of impaired proteolysis, proteasomes can still stimulate autophagy-dependent aggresome clearance by producing unanchored lysine (K)63-linked ubiquitin chains via the deubiquitinating enzyme Poh1. Unanchored ubiquitin chains activate ubiquitin-binding histone deacetylase 6, which mediates actin-dependent disassembly of aggresomes. This crucial de-aggregation of aggresomes allows autophagosomes to efficiently engulf and eliminate the protein aggregates. Interestingly, the canonical function of Poh1 involves the cleavage of ubiquitin chains en bloc from proteasomal substrates prior to their degradation by the 20S core, which requires intact 26S proteasomes. In contrast, here we present evidence that during aggresome clearance, 20S proteasomes dissociate from protein aggregates, while Poh1 and selective subunits of 19S proteasomes are retained as an efficient K63 deubiquitinating enzyme complex. The dissociation of 20S proteasome components requires the molecular chaperone Hsp90. Hsp90 inhibition suppresses 26S proteasome remodeling, unanchored ubiquitin chain production, and aggresome clearance. Ultimately, we hope to apply these molecular markers of inclusion body processing to identify the underlying lesion in aggregate prone neurodegenerative disease.</p> / Dissertation

<p> <p>&nbsp / </p> </p> <p align="left">This study utilized large-scale gene expression data to define the regulatory networks of genes expressing in the hippocampus to which multiple disease pathologies may be associated. Specific aims were: ident i fy key regulatory transcription factors (TFs) responsible for observed gene expression patterns, reconstruct transcription regulatory networks, and prioritize likely TFs responsible for anatomically restricted gene expression. Most of the analysis was restricted to the CA3 sub-region of Ammon&rsquo / s horn within the hippocampus. We identified 155 core genes expressing throughout the CA3 sub-region and predicted corresponding TF binding site (TFBS) distributions. Our analysis shows plausible transcription regulatory networks for twelve clusters of co-expressed genes. We demonstrate the validity of the predictions by re-clustering genes based on TFBS distributions and found that genes tend to be correctly assigned to groups of previously identified co-expressing genes with sensitivity of 67.74% and positive predictive value of 100%. Taken together, this study represents one of the first to merge anatomical architecture, expression profiles and transcription regulatory potential on such a large scale in hippocampal sub-anatomy.</p>

It has been postulated that there could be a connection between traumatic brain injury (TBI) and motor neuron disease (MND), including amyotrophic lateral sclerosis (ALS). As chronic traumatic encephalopathy (CTE) is caused by repeated TBI and is a newly examined disease, there has been little evaluation of the potential relationship between CTE and ALS. It was proposed that CTE is a risk factor for not only MND, but also ALS. There is significant evidence that even a single TBI is a risk factor for Parkinson's disease (PD), thought to be invoked by the inflammatory process that the brain undergoes following a TBI. General rigorous physical activity with trauma to the trunk or extremities does not appear to be a risk factor for ALS. However, physical activity with associated head traumas, especially repeated head traumas, does seem to increase the likelihood of developing ALS. The biological mechanism for this is suspected to be increase in free radicals during exercise in individuals who are predisposed to decreased antioxidant function. Additionally, individuals who have suffered repeated head trauma, even amongst the general population in a non-athletic setting, has been shown to drastically increase the individual's chance of developing ALS. CTE, which is most common in athletes, is speculated to be caused by TAR DNA-binding protein 43 (TDP-43), tau neurofibrillary tangle (NFT), and beta-amyloid (A-Beta) protein inclusions in brain tissue following a multitude of TBI during high level sport activity. There are individuals who suffer initially CTE, followed by ALS, indicating CTE is clearly a risk factor for ALS. Anatomically, the TDP-43, NTF, and A-Beta; inclusions are present in the brain tissue of both individuals with CTE alone as well as the individuals with CTE and ALS. The anatomic difference between these two pathologies is the inclusion of these three proteins in the spinal cord of ALS patients as well. Unfortunately, there are indications that previous studies of professional athletes and their development of ALS have presented with significant issues including confounding factors of the subpopulation and sample sizing. Additionally, the anatomical cause of TBI leading to ALS is still unknown. Further evaluation on the relationship between head injury and ALS must be dedicated to investigating the mechanism involved in developed PD versus ALS following TBI. The biologic sequence following TBI that leads to ALS must be examined and compared to individuals whom develop ALS but did not suffer TBI. Moreover, an assessment must be made to determine what causes some individuals to develop protein inclusions solely in the brain tissue, leading to CTE, and some individuals to have an advancement of the protein inclusions into the spinal cord, leading additionally to CTE followed by ALS.

A doença de Parkinson é a doença motora neurodegenerativa mais comum do mundo. Agregados proteicos contendo principalmente alfa-sinucleína é a principal marca da doença. Recentemente, tem sido demonstrado que defeitos na dinâmica mitocondrial e da autofagia são causados pelo acúmulo da proteína. No nosso estudo, foram utilizados neurônios derivados de SH-SY5Y ou de hiPSC de pacientes com a doença de Parkinson hereditária, além de leveduras para analisar a dinâmica mitocondrial e da autofagia e o envolvimento de proteínas desses processos na toxicidade da alfa- sinucleína. Foi observado a diminuição do tráfego mitocondrial em neurônios derivados das células SH-SY5Y que expressavam alfa-sinucleína A53T. Além disso a proteína mutante ainda levou ao aumento de espécies reativas de oxigênio, perturbação da autofagia e aumento da sinalização apoptótica. Os neurônios então foram tratados com NAP, um peptídeo neuroprotetor, que preveniu os efeitos tóxicos da alfa-sinucleína mutante. Leveduras contendo deleções nos genes Gem (Miro), Ypt53 (Rab5) e Atg8 (LC3) e expressando alfa-sinucleína dos tipos A30P e A53T, demonstraram que a toxicidade da alfa-sinucleína é dependente das disfunções na mitocôndria e na autofagia. A agregação da alfa-sinucleína A53T foi prevenida na ausência de Gem. Além disso, a toxicidade da proteína envolvendo a disfunção mitocondrial e sinalização apoptótica causada pelo estresse do ER foi dependente dos genes Gem e Atg8, respectivamente. Neurônios derivados de hiPSC de pacientes contendo a triplicação do gene da alfa-sinucleína, mostraram diminuição do transporte de mitocôndrias e do potencial de membrana da mitocôndria. Análises sobre a quantidade de vesículas lisossomais desses neurônios, demonstraram acúmulos dessas vesículas, sugerindo que a autofagia está alterada. Em um ensaio sobre a sensibilidade dos neurônios dopaminérgicos, foi observado que os neurônios contendo a alpha-sinucleína mutante são mais susceptíveis à rotenona, quando comparado com os neurônios dopaminérgicos do controle. A exposição à rotenona também causou mudanças na distribuição de mitocôndrias, sugerindo que o tráfego retrógrado da organela está alterado / Parkinson\'s disease (PD) is the most common motor neurodegenerative disease in the world. Protein aggregates containing mainly alpha-synuclein are a hallmark of disease. Mitochondria and autophagy defects have been suggested to be caused by alpha-synuclein toxicity. In this study, we investigated mitochondria and autophagy dynamics related to alpha-synuclein toxicity in neurons derived form SH-SY5Y cells, hiPSC from patients with familial PD or yeast. We found that SH-SY5Y neuroblastoma cells expressing A53T alfa- synuclein showed significantly inhibited mitochondrial trafficking. A53T alfa- synuclein also caused the highest increase in ROS production in the dysmobilized mitochondria in comparison to wild-type or A30P alfa- synuclein. Treatment with NAP, the 8 amino acid peptide identified as the active component of activity dependent neuroprotective protein (ADNP), completely annihilated the adverse effects of A53T on mitochondrial dynamics. During disruption of retrograde transport, we found disturbed autophagy and increased apoptosis signalization in neurons expressing A53T alpha-synuclein, suggest activation of the apoptosis pathway. Curiously, all groups expressing alpha-synuclein showed decreased levels of BCL-XL, revealing that mitochondria are susceptible to changes in the membrane potential in the presence of alphasynuclein. Nevertheless, treatment with NAP was effective in blocking the apoptosis pathway and restore autophagy. We created a model to study A30P and A53T alpha-synuclein toxicity related to Gem (Miro), Ypt53 (Rab5) and Atg8 (LC3) genes in Saccharomyces cerevisiae in which these genes were knocked down. We found that A30P alpha-synuclein toxicity was dependent on mitochondrial and autophagy dysfunction. A53T alpha-synuclein was more toxic than A30P alpha-synuclein, and its aggregation was dependent on Gem expression. A53T alpha-synuclein toxicity involving damaged mitochondrial and apoptotic signaling caused by ER stress was dependent on Gem and Atg8 genes, respectively. In a study involving dopaminergic neurons derived from hiPSCs from patients containing triplicated alpha-synuclein gene (SNCA3), we reported decreased mitochondrial trafficking and mitochondrial membrane potential, besides accumulation of lysosome vesicles. In a sensitivity assay, SNCA3 neurons demonstrated more susceptibility to rotenone toxicity, which alters intracellular mitochondrial distribution, impairing retrograde transport of the organelle

L'amyotrophie spinale infantile (SMA) est une maladie génétique autosomique récessive de l'enfant pour laquelle aucun traitement efficace n'existe. La SMA est caractérisée par la perte spécifique des motoneurones spinaux conduisant à une faiblesse musculaire sévère. Le décès des patients survient lorsque les muscles vitaux sont touchés. Cette maladie est causée par la mutation du gène Survival of Motor Neuron 1 (Smn1) conduisant à une diminution importante de l’expression de la protéine Survival of Motor Neuron (SMN). Tous les patients possèdent un ou plusieurs gènes copie de Smn1, le gène Smn2. Ces copies modulent la sévérité de la maladie en produisant une faible quantité de transcrits SMN complets, en particulier possédant l’exon 7, un exon alternatif qui code pour un domaine important pour que la protéine SMN soit fonctionnelle et stable. Des résultats récents, obtenus au laboratoire, indiquent que l'exercice physique retarde la mort des motoneurones, conduit à une augmentation du taux de maturation postnatale des unités motrices et déclenche l’expression du gène Smn2 chez des souris mimant la SMA de type II. Les premières données moléculaires suggèrent que les effets de l'exercice physique pourraient être relayés par la signalisation dépendante 1) des récepteurs au NMDA (Biondi et coll., J Neurosci, 2008) et/ou 2) du récepteur à IGF-1. Dans notre étude, nous avons d’abord testé les effets de l’activation directe des récepteurs au NMDA (NMDAR) dans un contexte de SMA. Nous montrons qu’une activation adéquate de ces récepteurs dans plusieurs modèles souris mimant les SMA sévères accélère la maturation postnatale des unités motrices, limite l'apoptose dans la moelle épinière et active l’expression du gène Smn2 favorisant l'expression de la protéine SMN. Ces effets bénéfiques sont dépendants du niveau d’activation des NMDARs et suggèrent que l'accélération de la maturation postnatale des unités motrices, induite par le NMDA, est indépendante du niveau d’expression de la protéine SMN. De manière importante, l’activation pharmacologique des NMDARs augmente fortement la durée de vie de deux modèles différents de souris mimant la SMA de type sévère. L'analyse des cascades de signalisation intracellulaire a révélé une altération inattendue des profils d’activation des voies de signalisation ERK et AKT/CREB, qui se rééquilibrent quand les NMDARs sont activés (Branchu et coll., J Neurosci, 2010).Comme la kinase ERK est constitutivement suractivée dans la moelle épinière des souris mimant la SMA, nous avons ensuite examiné son rôle potentiel dans la régulation de l'expression des gènes Smn2. Nous avons démontré que l'inhibition pharmacologique de la voie de signalisation MEK/ERK/Elk-1, notamment avec un médicament anti-cancéreux actuellement en essai clinique de phase 2, est bénéfique pour les souris mimant la SMA de type I. Nous avons identifié une relation croisée entre les voies de signalisation ERK et AKT impliquant la modulation, calcium-dépendante, de l'activité CaMKII. Ainsi, l'inhibition pharmacologique de ERK durant la phase symptomatique de la maladie chez ces souris, entraîne l'activation de la voie CaMKII/AKT/CREB et conduit à une augmentation significative de l’expression de la protéine SMN dans les motoneurones suite à une augmentation de la transcription du gène Smn2. Ces modifications sont corrélées avec une augmentation remarquable de la durée de vie et de la mobilité des souris et une neuroprotection des motoneurones spinaux. De plus, l’inhibition de ERK dans des cellules musculaires différenciées provenant de patients atteints de SMA de type II induit également une augmentation de l’activité de la voie AKT/CREB et de l’expression de SMN (Branchu et coll., J Neurosci, en révision positive). Enfin, nous avons montré que l'exercice physique est capable de diminuer l'expression du récepteur à l'IGF-1 (IGF-1R), qui est surexprimé dans la moelle épinière des souris mimant la SMA sévère... / Spinal muscular atrophy (SMA) is a severe autosomal recessive disease in childhood for which no efficient therapy is currently available. SMA is characterized by the specific loss of spinal motor neurons leading to a severe muscular weakness and death when vital muscles are affected. This disease is caused by mutation of the survival of motor neuron 1 (Smn1) gene leading to a deficiency of the Survival of Motor Neuron (SMN) protein expression. All patients retain one or more copies of the Smn2 gene, which modulates the disease severity by allowing a small amount of full-length SMN transcripts and stable SMN protein to be produced. Recent results in our laboratory indicate that physical exercise delays motor neuron death, leads to an increase in the motor-units postnatal maturation rate and trigger Smn2 gene expression in motor neurons. Furthermore, on the one hand, exercise is capable of specifically enhancing the expression of the gene encoding NR2A, the major activating subunit of the NMDA receptor in motor neurons. This subunit is known to be dramatically down-regulated in the spinal cord of severe SMA-like mice. Accordingly, inhibiting NMDA-receptor activity abolishes the exercise-induced effects on muscle development, motor neuron protection and life span gain (Biondi et al., J Neurosci, 2008). Thus, we tried to restore NMDA-receptor function as a therapeutic approach to SMA treatment. We demonstrated that an adequate NMDA receptor activation in severe SMA-like mouse model significantly accelerated motor-unit postnatal maturation, counteracted apoptosis in the spinal cord, and induced a marked increase in SMN expression resulting from a modification of Smn2 gene transcription pattern. These beneficial effects are dependent on the level of NMDA receptor activation since a treatment with high doses of NMDA led to an acceleration of the motor unit maturation but favored the apoptotic process and decreased SMN expression. Thus, these results suggest that the NMDA-induced acceleration of motor-unit postnatal maturation occurred independently of SMN. The NMDA receptor activating treatment strongly extended the life span in two different severe SMA-like mouse models. The analysis of the intracellular signaling cascades that lay downstream the activated NMDA receptor revealed an unexpected competition between the MEK/ERK/Elk-1 and the AKT/CREB signaling pathways for Smn2 gene regulation. Actually, the reactivation of the AKT/CREB pathway, thought calcium influx and the phosphorylation of CaMKII, opposed to MEK/ERK/Elk-1 inhibition, induces an enhanced SMN expression (Branchu et al., J Neurosci, 2010). On the other hand, exercise is capable of strongly decreasing the expression of IGF-1 receptor (IGF-1R); which is over-expressed in the spinal cord of severe SMA-like mice. We report that this reduction is also correlated with a reactivation of the AKT/CREB pathway and a MEK/ERK/Elk-1 inhibition. Therefore we generated an IGF-1R+/- SMA-like mouse model to investigate the functional link between IGF-1R expression level and the intracellular signaling pathway triggered in SMA spinal cord. We provided the first evidence that reducing the IGF-1R expression level is neuroprotective for SMA motor neurons, accelerates motor-unit postnatal maturation and leads to a remarkable increase in SMN expression and lifespan. The analysis of the intracellular signaling cascades revealed the same competition for Smn2 gene regulation. However, the activation of AKT/CREB is calcium-independent. In addition, we showed a drastic reduction of STAT3 phosphorylation and SOCS-1 and -3 expressions, which are over-expressed in SMA spinal cord and known to positively modulate ERK phosphorylation and negatively AKT (Data not published). Taken together all these data suggest new perspectives to therapeutic strategy, based on specific pharmacological correction, for SMA...

Typically, a Parkinson’s disease (PD) patient would display instances of tremor and bradykinesia (slowness of movement) at an early stage of the disease and later develop gait disturbances and postural instability. So, it is important to measure the tremor occurrences in subjects to detect the onset of PD. Also, it is equally essential to monitor the gait impairments that the patient displays, as the order at which the PD symptoms appear in subjects vary from one to another. The primary goal of this thesis is to develop a monitoring system for PD patients using wearable sensors. To achieve that objective, our work focused first on identifying the most significant features that would best distinguish between PD and normal healthy subjects. Here, the various gait and tremor features were extracted from the raw data collected from the wearable sensors and further analyzed using statistical analysis and pattern classification techniques to pick the most significant features. In statistical analysis, the analysis of variance (ANOVA) test was conducted to differentiate the subjects based on the values of the mean. Further, pattern classification was carried out using the Linear Discriminant Analysis (LDA) algorithm. The analysis of our results shows that the features of heel force, step distance, stance and swing phases contributed more significantly to achieving a better classification between a PD and a normal subject, in comparison with other features. Moreover, the tremor analysis based on the frequency-domain characteristics of the signal including amplitude, power distribution, frequency dispersion, and median frequency was carried out to identify PD tremor from different types of artifacts.

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第19315号 / 工博第4112号 / 新制||工||1634(附属図書館) / 32317 / 京都大学大学院工学研究科分子工学専攻 / (主査)教授 白川 昌宏, 教授 跡見 晴幸, 教授 梶 弘典 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM