Abstract
Aside from the classical motor symptoms, Parkinson’s disease also has various non-classical symptoms. Interestingly, orexin neurons, involved in the regulation of exploratory locomotion, spontaneous physical activity, and energy expenditure, are affected in Parkinson’s. In this study, we hypothesized that Parkinson’s-disease-associated pathology affects orexin neurons and therefore impairs functions they regulate. To test this, we used a transgenic animal model of Parkinson’s, the A53T mouse. We measured body composition, exploratory locomotion, spontaneous physical activity, and energy expenditure. Further, we assessed alpha-synuclein accumulation, inflammation, and astrogliosis. Finally, we hypothesized that chemogenetic inhibition of orexin neurons would ameliorate observed impairments in the A53T mice. We showed that aging in A53T mice was accompanied by reductions in fat mass and increases in exploratory locomotion, spontaneous physical activity, and energy expenditure. We detected the presence of alpha-synuclein accumulations in orexin neurons, increased astrogliosis, and microglial activation. Moreover, loss of inhibitory pre-synaptic terminals and a reduced number of orexin cells were observed in A53T mice. As hypothesized, this chemogenetic intervention mitigated the behavioral disturbances induced by Parkinson’s disease pathology. This study implicates the involvement of orexin in early Parkinson’s-disease-associated impairment of hypothalamic-regulated physiological functions and highlights the importance of orexin neurons in Parkinson’s disease symptomology.
Highlights
Parkinson’s disease (PD) is a neurodegenerative disease that is accountable for about 50% of all synucleopathies, which are diseases defined by abnormal accumulation of alphasynuclein (α-syn) aggregates
For the first time to the best of our knowledge, we showed that A53T p-α-syn accumulation-associated inflammation and astrogliosis was present in the lateral hypothalamus (LH) of A53T mice, which is represented by increased expression of GFAP and IBA1, and increased IBA1 cell counts in 7-month-old mice
Age-dependent exploratory locomotion, spontaneous physical activity (SPA), and EE disturbances are present in the A53T model of PD
Summary
Parkinson’s disease (PD) is a neurodegenerative disease that is accountable for about 50% of all synucleopathies, which are diseases defined by abnormal accumulation of alphasynuclein (α-syn) aggregates. PD affects 1–2 per 1000 of the population at any time, with 1% of people over the age of 65 and up to 5% of people over the age of 85 [1,2,3], and its prevalence is second only to Alzheimer’s disease. Classical hallmarks of PD include the presence of Lewy bodies and dopaminergic neuron loss in the substantia nigra which leads to signature movement disorders. In recent years, PD has become recognized as a multilayered disease. Neurodegeneration is not exclusive to dopaminergic neurons [3,5], and it is shown that mood, cognition, and metabolic impairments are present even prior to the onset of the hallmark motor impairments [6,7,8,9]
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