The Molecular Impact of Glucosylceramidase Beta 1 (Gba1) in Parkinson's Disease: a New Genetic State of the Art.

Parkinson's disease (PD) is a neurodegenerative disorder affecting 2-3% of those aged over 65, characterized by motor symptoms like slow movement, tremors, and muscle rigidity, along with non-motor symptoms such as anxiety and dementia. Lewy bodies, clumps of misfolded proteins, contribute to neuron loss in PD. Mutations in the GBA1 gene are considered the primary genetic risk factor of PD. GBA1 mutations result in decreased activity of the lysosomal enzyme glucocerebrosidase (GCase) resulting in α-synuclein accumulation. We know that α-synuclein aggregation, lysosomal dysfunction, and endoplasmic reticulum disturbance are recognized factors to PD susceptibility; however, the molecular mechanisms connecting GBA1 gene mutations to increased PD risk remain partly unknown. Thus, in this narrative review conducted according to a systematic review method, we aimed to present the main contributions arising from the molecular impact of the GBA1 gene to the pathogenesis of PD providing new insights into potential impacts for advances in the clinical care of people with PD, a neurological disorder that has contributed to the substantial increase in the global burden of disease accentuated by the aging population. In summary, this narrative review highlights the multifaceted impact of GBA1 mutations in PD, exploring their role in clinical manifestations, genetic predispositions, and molecular mechanisms. The review emphasizes the importance of GBA1 mutations in both motor and non-motor symptoms of PD, suggesting broader therapeutic and management strategies. It also discusses the potential of CRISPR/Cas9 technology in advancing PD treatment and the need for future research to integrate these diverse aspects for improved diagnostics and therapies.

Role of enteric glia and microbiota-gut-brain axis in parkinson disease pathogenesis.

The microbiota-gut-brain axis or simple gut-brain axis (GBA) is a complex and interactive bidirectional communication network linking the gut to the brain. Alterations in the composition of the gut microbiome have been linked to GBA dysfunction, central nervous system (CNS) inflammation, and dopaminergic degeneration, as those occurring in Parkinson's disease (PD). Besides inflammation, the activation of brain microglia is known to play a central role in the damage of dopaminergic neurons. Inflammation is attributed to the toxic effect of aggregated α-synuclein, in the brain of PD patients. It has been suggested that the α-synuclein misfolding might begin in the gut and spread "prion-like", via the vagus nerve into the lower brainstem and ultimately to the midbrain, known as the Braak hypothesis. In this review, we discuss how the microbiota-gut-brain axis and environmental influences interact with the immune system to promote a pro-inflammatory state that is involved in the initiation and progression of misfolded α-synuclein proteins and the beginning of the early non-motor symptoms of PD. Furthermore, we describe a speculative bidirectional model that explains how the enteric glia is involved in the initiation and spreading of inflammation, epithelial barrier disruption, and α-synuclein misfolding, finally reaching the central nervous system and contributing to neuroinflammatory processes involved with the initial non-motor symptoms of PD.

The role of gut-brain axis in a rotenone-induced rat model of Parkinson's disease.

Parkinson's disease (PD) is a widespread neurodegenerative condition affecting millions globally. This investigation centered on the gut-brain axis in a rotenone-induced PD rat model. Researchers monitored behavioral shifts, histological modifications, neurodegeneration, and inflammation markers throughout the rats' bodies. Results revealed that rotenone-treated rats displayed reduced exploration (p = 0.004) and motor coordination (p < 0.001), accompanied by decreased Nissl staining and increased alpha-synuclein immunoreactivity in the striatum (p = 0.009). Additionally, these rats exhibited weight loss (T3, mean = 291.9 ± 23.67; T19, mean = 317.5 ± 17.53; p < 0.05) and substantial intestinal histological alterations, such as shortened villi, crypt architecture loss, and inflammation. In various regions, researchers noted elevated immunoreactivity to ionized binding adapter molecule (IBA)-1 (p < 0.05) and reduced immunoreactivity to glial fibrillary acidic protein (p < 0.05) and S100B (p < 0.001), indicating altered glial cell activity. Overall, these findings imply that PD is influenced by gut-brain axis changes and may originate in the intestine, impacting bidirectional gut-brain communication.

Impact of dysexecutive syndrome in quality of life in Alzheimer disease: What we know now and where we are headed.

Alzheimer's disease (AD) is a common form of dementia that leads to multiple repercussions in the patient's life. This condition's clinical characteristics include loss of memory, temporal and spatial disorientation, language or executive dysfunction, and subsequent decline of social function. Dysexecutive syndrome (DS), the second most frequent neuropsychological dysfunction in AD, affects multiple brain areas and causes cognitive, behavioral, and emotional difficulties. We aimed to analyze the association between DS and AD and elucidate possible lack of evidence that may urge further research on this theme. Especially when dealing with such a disabling disease, where new findings can directly imply a better prognosis.

Premotor, nonmotor and motor symptoms of Parkinson's Disease: A new clinical state of the art.

Parkinson's Disease (PD) is a neurodegenerative disorder that affects dopaminergic neurons in the mesencephalic substantia nigra, causing a progressive clinical course characterized by pre-motor, non-motor and motor symptoms, which negatively impact the quality of life of patients and cause high health care costs. Therefore, the present study aims to discuss the clinical manifestations of PD and to make a correlation with the gut-brain (GB) axis, approaching epidemiology and therapeutic perspectives, to better understand its clinical progression and identify symptoms early. A literature review was performed regarding the association between clinical progression, the gut-brain axis, epidemiology, and therapeutic perspectives, in addition to detailing pre-motor, non-motor symptoms (neuropsychiatric, cognitive, autonomic, sleep disorders, sensory abnormalities) and cardinal motor symptoms. Therefore, this article addresses a topic of extreme relevance, since the previously mentioned clinical manifestations (pre-motor and non-motor) can often act as prodromal markers for the early diagnosis of PD and may precede it by up to 20 years.