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LRRK2 Inhibitors May Benefit Parkinson’s Patients With and Without Genetic Mutation, Study Finds

LRRK2

Inhibiting the activity of LRRK2 kinase — an enzyme whose mutated form is one of the most common genetic causes of Parkinson’s disease — may benefit patients both with and without this disease-related mutation, a study finds.

Molecules that block the activity of the LRRK2 kinase — such as DNL201 and DNL151, both being developed by Denali Therapeutics — are currently being tested in clinical trials.

The results of this study, “LRRK2 inhibition prevents endolysosomal deficits seen in human Parkinson’s disease,” were published in Neurobiology of Disease. The research was supported by the Michael J. Fox Foundation.

Mutations in the leucine rich repeat kinase 2 (LRRK2) gene are one of the most commonly known genetic causes of Parkinson’s disease. Evidence indicates that in people with idiopathic Parkinson’s, in which the disease has no known cause, the LRRK2 protein is overly active, regardless of the patient’s mutation status — whether or not they have a mutated LRRK2. That overly active protein leads to the malfunctioning of lysosomes, the special compartments within cells that digest and recycle different types of molecules. Lysosomal dysfunction is involved in the formation of  protein aggregates, or clumps, called Lewy bodies, which contribute to Parkinson’s and, therefore, neurodegeneration.

Therapies that can inhibit, or block LRRK2 are currently being tested in human clinical trials. However, it is still unclear whether blocking LRRK2 protein activity in people with idiopathic Parkinson’s can prevent lysosomal dysfunction and consequent neurodegenerative processes.

To learn more, investigators at the University of Pittsburgh now studied post-mortem brain samples, specifically from a motor brain region called the substantia nigra, which is severely damaged in Parkinson’s. The researchers characterized lysosomal abnormalities in the surviving dopaminergic neurons — the main source of dopamine, the loss of which is a hallmark of this disease — of idiopathic Parkinson’s patients.

When compared with healthy controls, Parkinson’s patients had more abnormal lysosomes. These changes occurred during the early stages of lysosomal development, the researchers found.

The team then investigated whether these post-mortem cellular findings could be replicated in an animal model of Parkinson’s. Rats were given two distinct dose regimens of rotenone, a pesticide that inhibits mitochondria, or the “powerhouses” of cells. Blocking mitochondria leads to cellular death and the onset of parkinsonian features.

Nine to 14 daily doses of rotenone reproduced many idiopathic Parkinson’s features, including lysosomal defects. This caused neurodegeneration in the striatum and substantia nigra, two brain areas involved in motor control.

Interestingly, five daily doses of the pesticide weren’t enough to cause cell death, but did increase the accumulation of Parkinson’s-related alpha-synuclein protein and produce changes in lysosomes.

“These data demonstrate that, in rotenone-treated rats, [alpha]-synuclein protein levels rise in the dopaminergic neurons prior to the onset of frank neurodegeneration,” the researchers said.

When overactive LRRK2 was blocked in rotenone-treated rats, the protein’s activity was reduced. That, in turn, improved the overall health of lysosomes and prevented the accumulation of alpha-synuclein. These effects were observed in animals without a genetic predisposition to develop Parkinson’s, suggesting that the LRRK2 kinase inhibitors may be effective beyond LRRK2-mutated patients.

“Our work suggests that drugs that block LRRK2, some of which have entered clinical trials, will be useful for people with typical Parkinson’s disease,” J. Timothy Greenamyre, MD, PhD, the study’s lead author, said in a press release.

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Behavioral, Metabolic Changes Linked to Sleep Restriction Could Foretell Parkinson’s, Animal Study Suggests

sleep restriction

Chronic sleep restriction alters movement, worsens cognitive dysfunction and induces changes in the levels of several amino acids — the building blocks of proteins — and other markers in rats with Parkinson’s, according to a new study.

According to researchers, these findings could enable the use of biomarkers to identify those at risk of developing the disease.

The study, “Chronic sleep restriction in the rotenone Parkinson’s disease model in rats reveals peripheral early-phase biomarkers,” was published in the journal Scientific Reports.

Non-motor symptoms of Parkinson’s typically appear years before significant loss of dopamine-producing neurons in the substantia nigra, an area of the brain key to motor control. One such symptom is impaired sleep. Both sleep disturbances and lifestyle-imposed sleep restrictions may contribute to cognitive decline and produce detectable alterations in the body.

However, it remains unclear whether sleep disturbances constitute a risk factor for developing Parkinson’s disease.

An international team of researchers from Brazil, the U.K. and the Netherlands used the rotenone-induced rat model of Parkinson’s disease to evaluate if chronic sleep restriction triggers metabolic changes, cognitive impairment, and changes in the circadian rhythm (the body’s internal clock).

When injected into the substantia nigra, rotenone, an agrochemical, induces similar changes to those seen in early Parkinson’s, including excessive daytime sleepiness, rapid eye movement (REM) sleep behavior disorder, insomnia, and disruption of spontaneous sleep.

The results revealed that, unlike rotenone, sleep restriction for 21 days (six hours per day) — by soft tapping or gently shaking the cage, or gently disturbing rats’ sleeping nest — did not induce loss of dopamine-producing nerve cells.

Animals subjected to sleep restriction did not show the decreased levels of locomotor activity (movement) observed in  rats injected with rotenone, as assessed using the open field test, which is an experimental test used to evaluate animals’ general locomotor activity levels, anxiety, and willingness to explore.

The object recognition task, which evaluates memory by measuring the time animals spend on a new object, revealed that sleep restriction aggravated rotenone-induced cognitive dysfunction. Sleep recovery for 15 days reversed rats’ memory deficits.

Sleep restriction also impaired the animals’ circadian rhythm, as they showed reduced activity during the first 75 minutes after lights-off (the night period  when rodents become more active) at weeks 2 and 3.

The investigators subsequently looked at biochemical alterations in blood plasma using two metabolic profiling approaches called global 1H nuclear magnetic resonance (NMR) spectroscopy and targeted liquid chromatography/mass spectrometry (LC/MS).

Sleep restriction increased plasma levels of amino acids leucine, isoleucine, valine, ornithine (reportedly increased in Parkinson’s), arginine, lysine, alanine, proline, phenylalanine (a precursor of dopamine) and carnitine, as well as 15 different phospholipids, which is a type of fat that is a key component of cellular membranes.

In contrast, sleep restriction lowered the levels of creatinine (a product of muscle metabolism), acetylcarnitine (a form of the amino acid L-carnitine), and kynurenine (a byproduct of the amino acid L-tryptophan and previously implicated in Parkinson’s), among other molecules.

When combined with rotenone, sleep restriction increased plasma concentrations of most of the same amino acids and also of 54 phospholipids, while decreasing creatinine and forms of amino acids such as acetylcarnitine. Sleep recovery completely eliminated the changes induced by sleep restriction and rotenone regarding these molecules.

A statistical analysis then revealed that the concentrations of isoleucine, leucine and kynerunine were different when comparing animals on sleep restriction to controls. Concentration of the amino acid methionine correlated with rats’ activities.

NMR data additionally showed rotenone alone induced higher levels of circulating triglycerides and lipoproteins as well as LDL cholesterol (the “bad” cholesterol). In contrast, sleep restriction alone did not alter biochemical parameters.

Combined with rotenone, sleep restriction led to a more pronounced increase in amino acids levels, including phenylalanine and tryptophan, whose metabolism has been found altered in early-stage Parkinson’s patients. Sleep recovery again eliminated these changes.

“If combined, our results bring a plethora of parameters that represents reliable early-phase [Parkinson’s] biomarkers which can easily be measured and could be translated to human studies,” researchers wrote. Identifying who is at risk of developing the disease “has the potential to improve therapeutic strategies and possibly delay or attenuate the onset of symptoms,” they added.

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