Title

Pathogenic changes and compensatory responses in a model of age-related neurodegeneration

Date of Completion

January 2002

Keywords

Biology, Neuroscience|Health Sciences, Pharmacology|Health Sciences, Pathology

Degree

Ph.D.

Abstract

Lysosomes are part of a dynamic system that is involved in replenishing a variety of cellular components. The more than 40 neurodegenerative diseases that arise from lysosomal dysfunction evidence the importance of these organelles in maintaining cell health. Enzymatic deficiencies induce the deposition of abnormally processed materials believed to contribute to the characteristic mental retardation and brain damage. The fact that age-related diseases exhibit similar changes has prompted investigation of whether lysosomal dysfunction contributes to these neurodegenerative disorders. Post-mortem analyses have demonstrated evidence of such a contribution, since the presence of protein aggregates (e.g., neurofibrillary tangles and amyloid plaques in Alzheimer's disease (AD) and huntingtin protein aggregates in Huntington's Disease (HD)) has been correlated with evidence of lysosomal dysfunction. Although to a lesser degree, normal aging is associated with lysosomal disruption, thus establishing the “age” risk-factor in the two diseases. In vivo and in vitro models also report that experimentally-induced lysosomal dysfunction promotes abnormal protein processing. Moreover, protein aggregates and lysosomal dysfunction have been linked to synaptic deterioration and cognitive decline. However, there is a lack of mechanistic data to explain the numerous connections. The work presented here studied the effects of lysosomal perturbation in cultured hippocampal slices to understand why synapses are particularly vulnerable. A general lysosomal inhibitor was found to induce a distinct pathogenic cascade including, abnormal aggregation, protein fragmentation and microtubule destabilization. Subsequent changes included severe impairment of neuronal transport and corresponding declines in the expression of synaptic proteins. The application of a lysosomal modulator markedly up-regulated the levels of lysosomal enzymes, reversing the pathologic steps, thereby validating the identified cascade. Although smaller, lysosomal activation events have been found associated with neurodegenerative disorders and were speculated to represent a kind of compensatory response. In conclusion, the results described show that lysosomal dysfunction leads to the disruption of microtubule-based transport mechanisms vital for synaptic maintenance. They also indicate that lysosomal activation in AD and HD represents an internal repair system that (1) is activated in response to lysosomal disturbances and (2) can be pharmacologically enhanced as a potential avenue for therapeutic intervention to treat an array of neurodegenerative diseases. ^