The Cognitive Heterogeneity of Parkinson’s Disease (Barker, Brayne, Robbins et al).
Over the last 12 years we have been following a group of newly diagnosed patients with Parkinson’s Disease (PD) from the county of Cambridgeshire. Every 18 months the patients have been contacted and re-examined using a number of assessments, especially a range of thinking and memory tasks. Over time it has become clear that there are two main types of PD, one in which the patients dement early and the other that have a more benign course. Those patients that dement earlier have subtle abnormalities on cognitive tasks when they first present to their GP with their PD and they are also older and tend to be of a particular genetic variant. This ability to recognise these two distinct types of PD has implications for how we can best use new therapies in the clinic for patients with these different types of PD.
Autophagy inducing drugs and neurodegenerative diseases (Rubinsztein, Barker et al.)
Intracellular protein misfolding/aggregation are features of many currently incurable late-onset neurodegenerative diseases, like Alzheimer’s disease, Parkinson’s disease and genetic disorders like Huntington’s disease (HD). The mutations causing many of these diseases confer novel toxic functions on their target proteins. We showed that one way in which these aggregate-prone proteins are removed is by a process called autophagy. Using an autophagy inducer, rapamycin, we have been able to reduce the levels of mutant huntingtin (the protien that lies at the heart of HD) and attenuated its toxicity in cells, and in various animal models of HD. We have now shown that autophagy is important in range of other related neurodegenerative diseases. In order to induce autophagy long-term, we have been striving to identify safer alternatives to the rapamycin. We have now demonstrated efficacy of one of such agent, rilmenidine, in a range of cell and animal HD models and are currently investigating this drug in a small trial in HD patients.
New gene found in a form of Hereditary Spastic Paraplegia (Reid)
An international research study headed by the Cambridge BRC researcher Dr Evan Reid and Dr Stephan Zuchner from the University of Miami identified mutations in a gene called reticulon 2 in a form of hereditary spastic paraplegia (HSP). HSP is characterised by progressive stiffness and weakness of the legs, caused by selective and specific degeneration of nerve fibres in the spine. In addition, the researchers showed that the reticulon 2 protein interacts with another HSP protein, spastin. Mutations in the gene encoding this latter protein cause the most common form of HSP. The reticulon 2 gene encodes a protein that plays a key role in shaping the endoplasmic reticulum, which is found within the cell itself. It has a number of functions, including protein synthesis, calcium signalling and regulation of other components of the cell. This study provides the most direct evidence to date that defects in how the endoplasmic reticulum is shaped could underlie nerve fibre degeneration.
The image shows a cell expressing reticulon 2 (red) and a form of the spastin protein that has been engineered to contain a disease-associated mutation (green).
Imaging networks and cognition in neurodegenerative disease: (Rowe, Barker, Robbins et al).
We have well established specialist clinics that integrate long term clinical care with research across a family of closely related neurodegenerative diseases: frontotemporal degeneration, progressive supranuclear palsy and corticobasal degeneration. In partnership with these patients and their carers, we have introduced innovations in cognitive examination, pharmacology and imaging of the brain’s structure, function and networks. The aim is to understand better how these illnesses lead to changes in behaviour, and to develop new ways to treat problems such as impulsivity, apathy, anti-social behaviour or inflexible thinking.