Neuropeptide Y gene transfer for neuroprotection in Machado-Joseph Disease

Tese de doutoramento em Ciências Farmacêuticas, na especialidade em Biotecnologia Farmacêutica, apresentada à Faculdade de Farmácia da Universidade de Coimbra ; Machado-Joseph disease or spinocerebellar ataxia type 3 (MJD/SCA3) is the most common dominantly inherited ataxia worldwide. It is caused by an over-repetition of the trinucleotide CAG, which translates into an expanded polyglutamine tract within the protein ataxin-3. This mutated protein acquires toxic properties promoting neurodegeneration responsible for a progressive impairment of balance and motor function. There is currently no therapy to prevent or slow down the progression of this neurodegenerative disorder. Neuropeptide Y (NPY) is an abundant peptide widely distributed through the mammalian brain, involved in several physiological functions. NPY demonstrated to be effective in controlling and alleviating neurodegeneration in different brain diseases, including Alzheimer’s, Parkinson’s and Huntington’s disease. Therefore, we evaluated NPY levels in postmortem patient samples and mouse models. Moreover, we investigated whether NPY gene transfer would control MJD-associated neuropathology and motor behavior defects in MJD mouse models. The hypothalamus is one of the main regulators of energy homeostasis, sleep and emotion. This brain region is affected by the pathogenic mechanisms of some neurodegenerative disorders, which has, in fact, been associated with some non-motor symptoms of Parkinson’s and Huntington’s disease patients. Considering that MJD patients present non-motor features, such as weight loss and sleep disturbances, we investigated the involvement of hypothalamus in MJD neuropathology, using MJD transgenic mice. This thesis is organized in 5 chapters. In chapter 1, a review about MJD and NPY, with emphases in NPY neuroprotective properties, is presented. In chapter 2, we evaluated striatal NPY levels in a lentiviral (LV)-based striatal MJD mouse model. Since NPY levels were reduced in mutant ataxin-3 transduced striata, we used this ...