Objective: To develop a treatment to stop or slow the progression of Parkinson’s disease.

Background: Parkinson’s disease (PD) is believed to be caused by the interaction between prolonged exposure to certain environmental factors and susceptible genes, and aging is the primary risk factor for idiopathic PD. One of the most consequential cellular changes associated with aging is mitochondrial dysfunction, which puts an energy constraint on the vital functions of all living cells in animals with advanced age. The dopamine (DA) neurons in the substantia nigra pars compacta (SNc) are believed to be particularly vulnerable to energy deficits because of their unique morphological and physiological features. The high energy cost to fire action potentials in SNc DA neurons places a constant metabolic stress on these neurons that may lead to oxidative stress, protein aggregation, elevated cytosolic calcium levels, and eventually cell death when the energy supply cannot keep up with the demand during aging. Here we test whether reducing the energy expenditure in DA neurons by inhibiting their activity during sleep, when DA is not needed for movement control, can protect DA neurons and slow the progression of PD.

Method: PD models: 6-20 week-old MitoPark mice. Treatments: DA neurons were silenced daily for 6-8 hours during sleep time, between 8-20 weeks of age, either by chemogenetic silencing or by pharmacological silencing. Outcomes: motor (open field and rotarod) and cognitive (Y-maze) functions measured at 10, 15 and 20 weeks of age; SNc DA neuron cell counting at 20 weeks of age.

Results: Silencing DA neurons for 6-8 hours per day, either chemogenetically or pharmacologically, improves motor and cognitive functions and reduces the loss of SNc DA neurons in MitoPark mice. Furthermore, silencing DA neurons during sleep does not cause motor or cognitive side effects, nor does it impair memory consolidation.

Conclusion: These findings suggest that daily sleep-time DA neuron silencing is a promising therapeutic strategy that may slow the progression of PD in humans.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/silencing-dopamine-neurons-during-sleep-slows-disease-progression-in-parkinsonian-mice/