Multiple factors have been hypothesized over the last century to be causative or contributory for Parkinson's disease. Hereditary factors have recently emerged as a major focus of Parkinson's disease research. Until recently most of the research on the etiology of Parkinson's disease concentrated on environmental factors, and the possibility that genetic factors contribute significantly to the pathogenesis of Parkinson's disease has been neglected. However, it has become increasingly apparent that even in sporadic cases, the disease most likely reflects a combination of genetic susceptibility and an unknown environmental insult. Moreover, the identification of genes and proteins that may cause hereditary parkinsonism substantially contributes to our ability to understand the pathogenesis of Parkinson's disease and may help in the early identification of the disease and its treatment. The discovery of alpha-synuclein mutations in families with autosomal dominant Parkinson's disease sheds light on its role in sporadic Parkinson's disease. It seems that this protein tends to aggregate when the cellular milieu is altered [14-16]. The question as to the exact changes that cause its deposition remains open. One of the major possibilities is oxidative stress [16]. The role of these aggregates in neuronal cell death is also still unclear. Transgenic mice expressing wild-type human alpha-synuclein developed progressive accumulation of alpha-synuclein and ubiquitin-immunoreactive inclusions in neurons in the neocortex, hippocampus and the substantia nigra. These alterations were associated with loss of dopaminergic terminals and motor impairments [24]. This finding suggests that accumulation of alpha-synuclein may play a causal role in sporadic Parkinson's disease as well. The parkin protein seems to be a crucial survival factor for nigral neurons [15]. The parkin protein is related to the ubiquitin pathway, which is important in the elimination of damaged proteins. Ubiquitin-mediated degradation of proteins plays a central role in the control of numerous processes, including signal transduction, receptor and transcriptional regulations, programmed cell death, and breakdown of abnormal proteins that may interfere with normal cell functions. Further studies on the function of Parkin protein and its relation to the ubiquitin pathway could elucidate at least one of the molecular mechanisms of nigral neuronal death. A mutation in the ubiquitin carboxy-teminal hydrolase L1 gene also implies the importance of the ubiquitin pathway in Parkinson's disease. Abnormal tau protein was found to be the cause of familial frontotemporal dementia and parkinsonism. It tends to form filamentous structures, which may lead to neuronal death. Elucidation of the molecular mechanism of neuronal death in this disease may contribute to our understanding of sporadic diseases with tau accumulation, such as corticobasal degeneration, progressive supranuclear palsy, Pick's disease, Alzheimer's disease and possibly also the pathogenesis of Parkinson's disease. Other genetic loci have been identified by linkage analysis of patients with familial parkinsonism. These loci conceal other genes and proteins that may be pivotal factors in the pathogenesis of Parkinson's disease. The discovery of genetic mutations in patients with parkinsonism may offer us new insights into the understanding of the pathways leading to neuronal death and development of Parkinson's disease. It may also help in the early identification of susceptible people to this disease and possibly in developing new treatment strategies.
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J Neuroeng Rehabil
January 2025
Department of Mechanical and Aerospace Engineering, University of Florida, PO Box 116250, Gainesville, FL, 32611, USA.
Background: Motor module (a.k.a.
View Article and Find Full Text PDFMol Neurodegener
January 2025
Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA.
Gastrointestinal (GI) involvement in Lewy body diseases (LBDs) has been observed since the initial descriptions of patients by James Parkinson. Recent experimental and human observational studies raise the possibility that pathogenic alpha-synuclein (⍺-syn) might develop in the GI tract and subsequently spread to susceptible brain regions. The cellular and mechanistic origins of ⍺-syn propagation in disease are under intense investigation.
View Article and Find Full Text PDFNat Med
January 2025
Department of Neurology & Neurological Sciences, Stanford Movement Disorders Center, Stanford University, Stanford, CA, USA.
Cerebral accumulation of alpha-synuclein (αSyn) aggregates is the hallmark event in a group of neurodegenerative diseases-collectively called synucleinopathies-which include Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. Currently, these are diagnosed by their clinical symptoms and definitively confirmed postmortem by the presence of αSyn deposits in the brain. Here, we summarize the drawbacks of the current clinical definition of synucleinopathies and outline the rationale for moving toward an earlier, biology-anchored definition of these disorders, with or without the presence of clinical symptoms.
View Article and Find Full Text PDFNPJ Parkinsons Dis
January 2025
Movement Disorders Unit, Department of Neurology, Hospital La Fe, Valencia, Spain.
Trends Neurosci
January 2025
Department of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada; Krembil Brain Institute, Toronto Western Hospital, Toronto, Ontario, Canada; Center for Advancing Neurotechnological Innovation to Application (CRANIA), Toronto, Ontario, Canada.
Parkinson's disease (PD) is a significant source of morbidity, especially with an aging population. Gait problems, particularly freezing of gait (FOG), remain a persistent issue, causing falls and reduced quality of life without consistent responses to therapies. PD and related symptoms have classically been attributed to dopamine deficiency secondary to substantia nigra degeneration from Lewy body (LB) and Lewy neurite (LN) infiltration.
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