Key factor in the neural death that causes Parkinson’s identified

A team of scientists from Karolinska Institutet and Ludwig Cancer Research has discovered how disruption of a developmental mechanism in the brain alters the very nerve cells that are most affected in Parkinson’s disease. The study, which is being published in the journal Nature Neuroscience, also explains how this disruption induces a lethal dysfunction in the internal, house-keeping processes of such neurons.

An incurable neurological disorder, Parkinson’s disease (PD) typically begins in patients as a mere tremor and progresses to a debilitating loss of control over movement and cognitive dysfunction, eventually leading to dementia and death. These symptoms are caused by the gradual wasting away of dopaminergic (DA) neurons, which respond to the neurotransmitter dopamine and are primarily clustered in the midbrain.

The causes of their wholesale death in PD, however, remain something of a mystery. In the current study, led by Professor Thomas Perlmann, researchers investigated a pair of closely related transcription factors – Lmx1a and Lmx1b – which are involved in the development of DA neurons. These developmentally vital transcription factors persist even after the neurons have matured. To find out what they do in mature neurons, the researchers painstakingly engineered mice in a manner that permitted them to delete the Lmx1a/b genes in DA neurons alone, and to do so at a time of their choosing.

“When we looked at the DA neurons that lacked the Lmx1a/b genes, those in adult mice had many of the same abnormalities you see in various stages of PD,” says Thomas Perlmann. "The engineered mice were also shown in behavioral tests to have poor memory and motor control, both of which are symptoms of PD.”

Affecting the neurons

The team found that midbrain DA neurons from patients with PD express far lower levels of the Lmx1b protein than do their non-PD counterparts. So the researchers looked into how the loss of Lmx1a and b was affecting the neurons. They found that Lmx1b, in particular, controls the expression of a number of genes central to a process known as lysosomal autophagy by which cells break down abnormally folded protein molecules so that they don’t poison the cell. This process is believed to be compromised in PD.

Treating young mice with a compound that boosts autophagy reversed the neural degeneration induced by loss of Lmx1b. In sum, the studies suggest the loss of Lmx1b expression is probably involved in the development of PD, that it induces a decline in the function of DA neurons by undermining autophagy and that this gradually sickens and then kills the DA neuron.

This study was supported by Ludwig Cancer Research, the European Union’s Seventh Framework Programme, the Swedish Strategic Research Foundation, the Swedish Research Council, Hjärnfonden and Parkinsonfonden. This news article is an abbreviated version of a press release from Ludwig Cancer Research.

Publication

Dopaminergic control of autophagic-lysosomal function implicates Lmx1b in Parkinson's disease
Ariadna Laguna, Nicoletta Schintu, André Nobre, Alexandra Alvarsson, Nikolaos Volakakis, Jesper Kjaer Jacobsen, Marta Gómez-Galán, Elena Sopova, Eliza Joodmardi, Takashi Yoshitake, Qiaolin Deng, Jan Kehr, Johan Ericson, Per Svenningsson, Oleg Shupliakov & Thomas Perlmann
Nature Neuroscience, AOP 27 April 2015, doi: 10.1038/nn.4004