New Genetic Mouse Model May Aid in Parkinson’s Research

Scientists say model may be key in developing potential therapies

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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A new Parkinson’s disease mouse model — carrying a common disease-associated mutation in both copies of the LRRK2 gene — recapitulates some motor and behavioral symptoms of the disease, while also showing mitochondrial abnormalities, a study showed.

Problems in mitochondria, known as the powerhouses of the body’s cells, are increasingly seen as key contributing factors for the loss of dopaminergic neurons (nerve cells) that characterize Parkinson’s.

These findings suggest that this new mouse model of Parkinson’s may be used to better understand the disease’s underlying mechanisms, including those related to mitochondria, which may help identify new potential targets and therapies, the researchers noted.

The study, “Homozygous mutation of the LRRK2 ROC domain as a novel genetic model of parkinsonism,” was published in the Journal of Biomedical Science.

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Parkinson’s is characterized by the progressive loss of dopaminergic, or dopamine-producing, neurons in the brain. Dopamine is a major chemical messenger, and plays a vital role both in learning and motivation, and in the regulation of movement. Its loss causes the disease’s characteristic motor and nonmotor symptoms.

The role of LRRK2

Mutations in the LRRK2 gene are one of the most frequent causes of both sporadic and familial Parkinson’s. Increasing evidence suggests such mutations may contribute to the disease through problems in molecule transport, breakdown, and recycling pathways, as well as in mitochondrial function.

In Parkinson’s, LRRK2 mutations often occur as different alterations in both copies of the gene. However, a large number of patients worldwide carry one of the two most common LRRK2 mutations — G2019S and R1441G — in both gene copies. When a specific mutation is present at both copies of a gene it is said to be homozygous.

Noting the limited number of Parkinson’s mouse models associated with homozygous LRRK2 mutations, two researchers in Taiwan decided to develop a new one. Their animals carried R1441G, the second-most common mutation, in both copies of a genetically-inserted human LRRK2 gene.

To conduct appropriately controlled analysis, the researchers compared the motor, nonmotor, and molecular features of the new model with those of mice carrying two healthy copies of the human LRRK2 gene.

The team noted that mice with the human LRRK2 gene, used as controls, showed hyperactivity and better motor function relative to normal mice, which is consistent with findings from previous studies. This further strengthened the importance of using such a control in this type of comparative analysis.

Compared with age-matched control mice, R1441G homozygous mice showed obvious age-dependent motor deficits that resembled the general bradykinesia, or slow movement, of Parkinson’s patients.

Their reduced gait velocity, stride length, and cadence were similar to the “small steps, slow and shuffling gait-observed in [Parkinson’s disease] patients,” the researchers wrote. Gait is the pattern of limb movement during locomotion, or movement from one place to another.

Mice with homozygous LRRK2-R1441G mutations also showed impaired vigilance and/or exploration behavior and signs of anxiety.

These findings “demonstrated both motor and cognitive dysfunction in the [R1441G homozygous mouse], which resembles the motor and nonmotor symptoms in human PD,” the researchers wrote.

The new mouse model showed no significant change in the number of dopaminergic neurons — but had a significant reduction in the number of nerve terminals of these neurons.

This suggests dysfunction of nerve terminals occurs prior to dopaminergic neuron loss in this mouse model, which is consistent with data from other animal models and Parkinson’s patients.

Notably, there was a significant accumulation of vesicles involved in molecule breakdown and recycling inside dopaminergic neurons in R1441G homozygous mice relative to controls.

These Parkinson’s mice also showed smaller mitochondria and significantly increased levels of proteins involved in mitochondria fragmentation relative to controls. Such fragmentation is the breakdown of these energy-producing cells.

Generally similar, but often milder, trends were observed for mice carrying only one human LRRK2-R1441G mutation, when compared with controls.

These findings highlighted that these R1441G homozygous mice reproduce “some [features] of Parkinsonism in terms of both motor and behavioral dysfunction,” the researchers wrote.

“This mutant animal model of PD might be used to study the mechanisms of mitochondrial dysfunction and explore potential new drug targets,” they added.

Further studies, however, are needed “to elucidate the usefulness” of these mice “for pre-clinical modeling of PD,” the researchers noted.

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