Abstract
Lewy body diseases, such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), are associated with a wide range of nonmotor symptoms (NMS), including cognitive impairment, depression and anxiety, sleep disorders, gastrointestinal symptoms, and autonomic failure. The reason why such diverse and disabling NMS have not been weeded out but have persisted across evolution is unknown. As such, one possibility would be that the NMS might be somehow beneficial during development and/or reproductive stages, a possibility consistent with our recent view as to the evolvability of amyloidogenic proteins (APs) such as α-synuclein (αS) and amyloid-β (Aβ) in the brain. Based on the heterogeneity of protofibrillar AP forms in terms of structure and cytotoxicity, we recently proposed that APs might act as vehicles to deliver information regarding diverse internal and environmental stressors. Also, we defined evolvability to be an epigenetic phenomenon whereby APs are transgenerationally transmitted from parents to offspring to cope with future brain stressors in the offspring, likely benefitting the offspring. In this context, the main objective is to discuss whether NMS might be relevant to evolvability. According to this view, information regarding NMS may be transgenerationally transmitted by heterogeneous APs to offspring, preventing or attenuating the stresses related to such symptoms. On the other hand, NMS associated with Lewy body pathology might manifest through an aging-associated antagonistic pleiotropy mechanism. Given that NMS are not only specific to Lewy body diseases but also displayed in other disorders, including amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD), these conditions might share common mechanisms related to evolvability. This might give insight into novel therapy strategies based on antagonistic pleiotropy rather than on individual NMS from which to develop disease-modifying therapies.
Highlights
It is well established that synucleinopathies, including Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), are characterized by a number of nonmotor symptoms (NMS), such as cognitive impairment, depression and anxiety, sleep difficulties, gastrointestinal disturbance, and autonomic failure
Increasingly clear that NMS are important early biomarkers as well as targets for disease-modifying therapy for synucleinopathies, such as PD, DLB, and MSA, the mechanisms by which NMS are involved in the pathogenesis of the disease have not been fully understood
We hypothesized that stress information derived from both MSand NMS-relevant neurons might be integrated into the diverse structures of αS protofibrils and are transgenerationally transmitted, which is probably beneficial to ward against forthcoming stressors in offspring, i.e., evolvability
Summary
It is well established that synucleinopathies, including PD, DLB, and MSA, are characterized by a number of NMS, such as cognitive impairment, depression and anxiety, sleep difficulties, gastrointestinal disturbance, and autonomic failure. Because some NMS occur in the prodromal disease stages, NMS are both mechanistically and therapeutically important [1, 2]. In this field, there has been great interest in better understanding NMS, a topic which has Parkinson’s Disease been prominently reviewed [3,4,5,6,7,8,9]. The mechanisms which underlie NMS in neurodegenerative diseases remain obscure. NMS may manifest as symptoms of aging-associated neurodegenerative disease through an antagonistic pleiotropy mechanism in the parental brains. We propose that a better understanding of this hypothetical view would facilitate development of a therapy strategy against NMS in synucleinopathies
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