Donders Institute for Brain, Cognition and Behaviour
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Thesis defense Giuseppe Manfré (Donders series 324)

6 July 2018

Promotor: prof. dr. B. Roozendaal
Copromotors: dr. J. Homberg, dr. J. van der Harst

Pheno-Ratting: towards the Characterization of Motor and Psychiatric Phenotypes in the BACHD Rat Model of Huntington Disease

Neuropsychiatric and neurological disorders constitute a major health problem in Europe, and their impact on public health and society is increasing with the aging of the population. In 20061 the World Health Organization estimated that neurological disorders, rang i ng from epi Ie psy to Alzheimer d i sease, fro m stroke to h ead ache d isord ers1 affect up to one billion people worldwide. One particularly relevant neurological disorder in the framework of the foregoing concerns is Huntington disease {HD). HD is an autosomal-dominantly inherited, fatal, neu­rodegenerative disorder. lt is caused by an unstable, expanded CAG base triplets in the coding region of the Huntingtin gene (HTT)1 resulting in an abnormal polyglutamine sequence in the huntingtin protein {htt). HD patients typically suffer from a triad of movement, psychiatrie and cognitive symptoms. The on set of the symptoms1 that can va ry be twee n i nd ivi d ua Is and affected mem be rs of the sam e fam i ly, usual I y occ u rs in mid-adulthood {30-40 years old)1 but the on set of disease may be earlier or later in life. The diagnosis of adult-onset HD typically involves involuntary motor abnormalities and chorea that aften decrease in a late stage1 when parkinsonism, dystonia and rigidity dominate. In the early stages patients have deficits in executive system functioning, short-term memory and visuospatial functioning. The later stages are characterized by bradykinesia, spasticity, dysarthria, dysphagia and incontinence. In addition to motor abnormalities, cognitive decline and personality changes are part of HD, and, like motor impairments, they deteriorate gradually. Additionally, cognitive deficits progress to more widespread global subcortical dementia with apathy1 impulsiveness and depression, resulting in a negative impact in social life and interpersonal relations. Less common are delusional depression or schizophrenia-like-psychosis, which might require psychiatrie treatment Since the discovery of the HTTmutation 25 years ago, more than 13,000 papers have been published on HD, approximately half of which re late to attempts to model various aspects of the disease. Thus, despite the considerable progress in our understanding of the disease, an effective treatment that either prevents or slows the pace of HD remains out of reach. The slow rate of progression of HD often necessitates lengthy and therefore costly clinical trials. In addition, the number of patients with HD who are available to participate in such trials is limited, which means that a relatively small numb er of compounds can be tested every time. Therefore, one of the most important challenges for finding more effective drugs for bra in disorders is the development of model systems that translate to human pathology and are predictive of clinical efficacy. Accordingly, part of that research effort involves identifying suitable ani mal mode Is that provide a valid representation of the pathological and behavioral profile of the human disease and that can serve for the identification of therapeutic candidates and navel approaches to therapy.