Synaptopathic mechanisms of neurodegeneration and dementia: insights from Huntington's disease

Dementia encapsulates a set of symptoms that include loss of mental abilities such as memory, problem solving or language, and reduces a person's ability to perform daily activities. Alzheimer's disease is the most common form of dementia, however dementia can also occur in other neurological disorders such as Huntington's disease (HD). Many studies have demonstrated that loss of neuronal cell function manifests pre-symptomatically and thus is a relevant therapeutic target to alleviate symptoms. Synaptopathy, the physiological dysfunction of synapses, is now being approached as the target for many neurological and psychiatric disorders, including HD. HD is an autosomal dominant and progressive degenerative disorder, with clinical manifestations that encompass movement, cognition, mood and behaviour. HD is one of the most common tandem repeat disorders and is caused by a trinucleotide (CAG) repeat expansion, encoding an extended polyglutamine tract in the huntingtin protein. Animal models as well as human studies have provided detailed, although not exhaustive, evidence of synaptic dysfunction in HD. In this review, we discuss the neuropathology of HD and how the changes in synaptic signalling in the diseased brain lead to its symptoms, which include dementia. Here, we review and discuss the mechanisms by which the 'molecular orchestras' and their 'synaptic symphonies' are disrupted in neurodegeneration and dementia, focusing on HD as a model disease. We also explore the therapeutic strategies currently in pre-clinical and clinical testing that are targeted towards improving synaptic function in HD.