Alpha-synuclein in LRRK2 brains
9 July 2013
First author Adamantios Mamais tells us about his recent publication in Neurobiology of Disease: At the Queen Square Brain Bank (part of the UCL Institute of Neurology) we hold a large collection of post-mortem human brain tissue from patients with neurodegenerative diseases including Parkinson’s disease (PD); a debilitating neurological disorder that affects the central nervous system. In the United States alone about 50,000 new cases are reported every year. The main symptoms include tremor, slow movement, rigid limbs and a shuffling gait while these worsen with time.
A common pathological characteristic in PD patients is the abnormal accumulation of a protein named α-synuclein that can be seen under the microscope in neurons in the brain. This protein aggregation forms what we call Lewy bodies, named after the prominent neurologist Dr Frederic Lewy that characterised them in 1912. This is also followed by α-synuclein becoming very insoluble in detergents in the lab. In fact protein aggregation is a common pathological phenomenon seen in other neurodegenerative diseases like Alzheimer’s disease and frontotemporal dementia.
Our goal is to understand what causes these changes in α-synuclein. In 5% of PD patients the disease is directly caused by genetic mutations that can be inherited. We hold four post-mortem PD cases from patients that carried the most prevalent mutation of the inherited form of the disease, the LRRK2 mutation G2019S. By studying these brains we found a striking difference in the insolubility properties of α-synuclein compared to brains of PD patients that did not carry mutations.
This is the first time that a difference in α-synuclein properties has been discovered between genetic and not-genetic PD and can give us clues as to the effect of the mutation in abnormal protein aggregation and neurodegeneration. Most importantly this suggests that the real detrimental effect in G2019S PD may not be caused by α-synuclein becoming insoluble while it is being deposited in Lewy bodies.
Mamais, A., Raja, M., Manzoni, C., Dihanich, S., Lees, A., Moore, D., Lewis, P., Bandopadhyay, R., 2013. Divergent a-synuclein solubility and aggregation properties in G2019S LRRK2 Parkinson’s disease brains with Lewy Body pathology compared to idiopathic cases. Neurobiol Dis.