Parkinson's Spectrum Mechanisms in Pregnancy: Exploring Hypothetical Scenarios for MSA in the Era of ART

Abstract

Multiple System Atrophy (MSA) is a rare, rapidly progressive neurodegenerative disorder marked by autonomic dysfunction, parkinsonism, and cerebellar ataxia. While predominantly affecting individuals in their fifth or sixth decade, advancements in assisted reproductive technologies (ART) have created new clinical scenarios involving pregnancies in women within MSA's typical onset range. Given the scarcity of documented MSA pregnancies, this review leverages insights from related Parkinson's spectrum mechanisms to explore hypothetical scenarios for how pregnancy-induced physiological changes might influence MSA progression. Pregnancy-induced hormonal fluctuations, including elevated estrogen and progesterone levels, may modulate α-synuclein aggregation and neuroinflammatory pathways. Immune adaptations, such as fetal microchimerism and Th2-biased immune profiles, introduce additional complexities, particularly in donor embryo pregnancies involving complex microchimerism. Metabolic demands and oxidative stress further intersect with these mechanisms, potentially accelerating disease progression. We analyze existing literature and theoretical models, emphasizing the need for interdisciplinary research. Clinical implications are discussed to propose evidence-based strategies for optimizing maternal-fetal outcomes. This paper identifies critical knowledge gaps and proposes avenues for future investigation to optimize maternal-fetal outcomes in this unique and underexplored clinical intersection.

Keywords: Parkinson’s spectrum; assisted reproductive technologies; epigenetics; hormonal changes; microchimerism; multiple system atrophy; pregnancy; α-synuclein.

Figure 1

Molecular and cellular mechanisms in MSA pathophysiology—the fundamental mechanisms implicated in the pathophysiology of MSA include α-syn aggregation and toxic species formation, the development of glial cytoplasmic inclusions in oligodendrocytes, and disruptions in cellular energy pathways driven by mitochondrial dysfunction. Additionally, genetic and epigenetic factors, protein aggregation and misfolding pathways (proteostasis and clearance), along with the role of ROS (reactive oxygen species) and exosomes, and the interplay between neurodegeneration progression and latency are highlighted as interconnected contributors to disease development.

Figure 2

α-syn aggregation and pathological outcomes. Flow diagram representing how α-syn accumulation affects oligodendrocytes, leading to MSA pathology, potentially accelerated by pregnancy-induced stress factors.

Figure 3

Balancing hormonal effects on neuronal health: illustration of hormonal influence on neurological conditions. Pregnancy-related hormones can exert protective effects on neuronal health, yet under conditions of imbalance, may increase vulnerability to neurodegenerative processes.

Figure 4

Microchimerism and immune modulation during pregnancy. The circles indicate hypothesized cytokine-mediated interactions between maternal and fetal immune systems, potentially affecting maternal neurological health, including MSA. Early pregnancy features a pro-inflammatory (Th1) immune environment with high NK cell activity. As pregnancy progresses, the immune response shifts toward an anti-inflammatory (Th2) profile, characterized by increased regulatory Treg activity, enhanced immune tolerance, and reduced systemic inflammation. Although generally protective, these immune adaptations in combination with fetal microchimerism could paradoxically influence maternal susceptibility to neuroinflammatory or neurodegenerative conditions. Following delivery, a postpartum immune recovery, marked by a reactivation of pro-inflammatory pathways, combined with the long-term persistence of fetal microchimeric cells in maternal tissues, may further contribute to immune dysregulation and neurological vulnerability.

Figure 5

Key physiological changes during pregnancy, including hormonal fluctuations, immune adaptations, metabolic stress, and cardiovascular changes, interact with MSA pathophysiology. These changes may influence neuroinflammation, α-syn aggregation, and mitochondrial function, potentially altering disease progression.

Figure 6

Understanding key clinical pathways for navigating MSA in pregnancy. The diagram illustrates five critical pathways converging to achieve optimal outcomes for mother and fetus.

Figure 7

Critical research gaps in understanding the relationship between MSA and pregnancy include limited clinical data, mechanistic insights, and safety considerations for therapeutic approaches. Addressing these gaps is essential for advancing maternal and fetal care in this context.

Figure 8

A proposed framework for addressing the interplay of MSA and pregnancy, emphasizing a stepwise approach from foundational research to optimized maternal-fetal outcomes. The framework includes discovery of novel pathways and biomarkers, clinical studies, therapeutic development, and evaluation to inform evidence-based care.