Diss. (sammanfattning) Uppsala : Uppsala universitet, 2005. / Härtill 7 uppsatser.

Thesis (MHSc--Health Science) -- Auckland University of Technology, 2003. / Appendices A and B are not included in e-thesis. Also held in print (148 leaves, 30 cm.) in Akoranga Theses Collection (T 616.83 BRO)

Dissertation (Ph.D.).--University of Texas Graduate School of Biomedical Sciences at San Antonio, 2007. Thesis (M.S.) --University of Texas Graduate School of Biomedical Sciences at San Antonio, 2007. / Vita. Includes bibliographical references.

Thesis (Ph. D.)--Ohio State University, 2006. / Title from first page of PDF file. Includes bibliographical references (p. 103-116).

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects between 14,000 to 15,000 Americans. The upper and lower motor neurons degenerate, which eventually causes muscle paralysis, atrophy, and ultimately death from respiratory failure. It has a high treatment cost as well as a high toll on the patient and their families and friends. Currently, there are only two drugs approved by the FDA for the treatment of ALS: riluzole and edaravone. Research is constantly being conducted to understand and develop further treatment modalities, however, many drugs have failed to demonstrate significant improvement in phase III trials. One of the pathophysiology that these drugs, including riluzole, target is excitotoxicity of the motor neurons. This review will briefly expand upon the different trials that were conducted targeting the excitotoxicity pathway. Although they may have not been successful in prolonging survival in ALS patients, we can learn from these studies and build upon them.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2010.

The human VAMP-associated protein B (hVAPB) has been shown to cause a range of motor neurodegenerative diseases, including amyotrophic lateral sclerosis 8 (ALS8) and spinal muscular atrophy (SMA). However, the molecular mechanisms underlying VAPB-induced neurodegeneration remain elusive. We sought to address this question by identifying VAPB interacting proteins, which may be affected by the disease causative mutations. Using a combination of biochemical and genetic approaches in Drosophila, we confirmed the evolutionarily conserved phosphoinositide phosphatase Sac1 (Suppressor of Actin 1), as a DVAP binding partner and showed that the two proteins colocalise in the endoplasmic reticulum. We also show that DVAP function is required to maintain normal levels of phosphoinositides (PIs) and that downregulation of either Sac1 or DVAP at the larval neuromuscular junction (NMJ) affects a number of synaptic processes, including axonal transport, synaptic growth, microtubule integrity and localisation of several postsynaptic components. We found that double knock down of DVAP and Sac1 induces no further increase in the severity of the mutant phenotypes when compared to either single mutant alone. This, together with the similarity in mutant phenotypes, indicates that the two genes function in a common pathway. In flies carrying the ALS8 mutation (DVAP-P58S), we observed reduced viability, locomotion defects and early death in surviving adults, closely matching the phenotypes of both DVAP and Sac1 downregulation. Additionally, transgenic expression of DVAP-P58S in the motor system elicits synaptic defects similar to those of either Sac1 or DVAP loss-of-function, including an increase in the levels of PtdIns-4-Phosphate (PI4P), the substrate of Sac1. Consistent with these observations, we found that Sac1 is sequestered into DVAP-P58S mediated aggregates and that downregulation of PI4P in neurons rescues the neurodegenerative and the synaptic phenotypes associated with DVAP-P58S transgenic expression. Together our data unveil a previously unknown function for Sac1 in neurodegeneration and synaptic function, as well as provide evidence for a dominant negative mechanism for phosphoinositide-mediated ALS8 pathogenesis. We also highlight a causative role for increased PI4P levels in VAPB-P56S induced neurodegeneration.

published_or_final_version / Anatomy / Doctoral / Doctor of Philosophy

This PhD thesis examines the relationship between Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal dementia (FTD). ALS is a rapidly progressive neurodegenerative movement disorder characterized by muscle weakness, spasticity and abnormal reflexes. In a very small subset of patients (5-15%), ALS is associated with FTD. Furthermore, a larger subset of patients who do not suffer from overt dementia, develop subtle deficits in cognition and behaviour (up to 50%). The changes have mostly been observed in the domains of executive functions, language and behavioural functioning. These observations have led some researchers to propose a continuum of dysfunction between ALS and FTD, ranging from an absence of neuropsychological abnormalities to mild, subclinical changes to a profile consistent with a full-blown FTD-syndrome in ALS. FTD consists of three subsyndromes; the first ‘executive-behavioural’ type, frontal variant FTD (fvFTD), is predominantly characterized by behaviour abnormalities, difficulties with using strategies and social judgement. In contrast, the other two types mainly involve problems with ‘language’, including a central degradation of knowledge for words, objects, people (semantic dementia; SD) as well as complications with speaking, spelling and the sounds of language (progressive non-fluent aphasia; PNFA). The current study aims to explore whether the cognitive-behavioural deficits found in nondemented ALS-patients can be classified as subclinical forms of the first two FTDsyndromes, i.e. fvFTD and SD. In addition, the study further examined whether executive and language impairments co-exist or rather occur independently. To answer the research questions, a battery of neuropsychological tests was employed, adapted to patients’ speech and motor disabilities, as well as behavioural questionnaires. The data revealed there was evidence of both executive and language involvement characteristic of FTD, albeit to a subtle extent. ALS-patients showed deficits on a test of Theory of Mind (ToM). On this test, participants were asked to judge the thoughts and feelings of another, using the direction of eye gaze, a cue considered to be important for social interaction. Results indicated that ALS patients had difficulties with affective ToM, i.e. recognizing feelings of others, and this effect was not driven by perceptual or attentional difficulties. In addition, patients exhibited a subtle deficit with empathy as well as a range of behavioural abnormalities. Furthermore, ALS-patients showed abnormal performance on a complex multi-modal semantic association task which involved assigning the correct picture iii to the sound of an object. This central deficit emerged in the presence of normal audio-visual information processing and episodic memory functions. Moreover, a category-specific deficit for man-made objects was detected in patients. Individual case-analyses showed that various subsets of patients were impaired on the language and executive tasks. These analyses also showed that executive and language problems can occur independently as well as simultaneously in patients with ALS. In addition, analysis of individual cases revealed that some patients’ performance on the decision making tasks was similar to that found in patients with either orbitofrontal or dorsolateral dysfunction, while there was little if any evidence of a pattern of impairment similar to that seen with anterior cingulate dysfunction. The observed difficulties with social cognition and semantic processing indicate that executive and language problems, characteristic of the two FTD syndromes, can be detected in patients with classical ALS.

Amyotrophic Lateral Sclerosis (ALS) is a debilitating and fatal neurodegenerative disease affecting upper and lower motor neurons. Though studied for over two decades since the first ALS-associated genetic mutation was discovered, researchers have yet to uncover the pathological processes that lead to progressive degeneration of motor neurons in ALS, or to develop effective treatments. One prominent hypothesis proposes that excitotoxicity caused by increased motor neuron firing plays a role in ALS pathogenesis. While prior studies reported increased action potential firing in early postnatal ALS-model motor neurons in vivo, it remains unknown whether the increased activity stems from increased intrinsic excitability of ALS motor neurons or from increased excitatory drive, and whether these changes are transient or persist into adulthood, when ALS symptoms emerge. In this thesis, I circumvented the difficulties in standard measurement of electrophysiological properties of adult spinal motor neurons in vivo by relying on the visualization of the axon initial segment, a subcellular structure known to undergo compensatory structural changes in response to perturbations in excitatory input. I discovered that cultured motor neurons derived from stem cells of the SOD1G93A mouse model of ALS display shortened axon initial segments and hypoexcitable electrophysiological properties. The shortening of the axon initial segment is compensatory, as ALS motor neurons receive increased numbers of excitatory inputs and manifest increased spontaneous activity. Remarkably, similar shortening of the axon initial segment was detected in early presymptomatic spinal motor neurons in vivo. The shortened axon initial segment persists into the symptomatic stages and is particularly pronounced in motor neurons containing p62 immunoreactive aggregates and neurons exhibiting swollen mitochondria, two signs of stress and neurodegeneration in the disease. Based on these observations I propose that early in the presymptomatic stages of the disease, spinal motor neurons recruit excessive excitatory inputs, resulting in their increased activity that is in part compensated by shortening of the axon initial segment. This state persists and becomes even more pronounced in motor neurons exhibiting biochemical changes preceding neurodegeneration. While these observations support the potential role for excitotoxic stress in spinal ALS motor neurons, I paradoxically observed the opposite phenotype in ALS-vulnerable cranial motor neurons in the brainstem of the SOD1G93A animals, raising the possibility that the cellular stress that drives the neurodegeneration in ALS is motor neuron subtype specific.