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Parkinson's disease (PD) is the second most common neurodegenerative disorder in the aging population, and no disease-modifying therapy has been approved to date. The pathogenesis of PD has been related to many dysfunctional cellular mechanisms, however, most of its monogenic forms are caused by pathogenic variants in genes involved in endolysosomal function (LRRK2, VPS35, VPS13C, and ATP13A2) and synaptic vesicle trafficking (SNCA, RAB39B, SYNJ1, and DNAJC6). Moreover, an extensive search for PD risk variants revealed strong risk variants in several lysosomal genes (e.g., GBA1, SMPD1, TMEM175, and SCARB2) highlighting the key role of lysosomal dysfunction in PD pathogenesis. Furthermore, large genetic studies revealed that PD status is associated with the overall "lysosomal genetic burden", namely the cumulative effect of strong and weak risk variants affecting lysosomal genes. In this context, understanding the complex mechanisms of impaired vesicular trafficking and dysfunctional endolysosomes in dopaminergic neurons of PD patients is a fundamental step to identifying precise therapeutic targets and developing effective drugs to modify the neurodegenerative process in PD. [ABSTRACT FROM AUTHOR]

The progressive aging of the population and the fact that Parkinson's disease currently does not have any curative treatment turn out to be essential issues in the following years, where research has to play a critical role in developing therapy. Understanding this neurodegenerative disorder keeps advancing, proving the discovery of new pathogenesis-related genes through genome-wide association analysis. Furthermore, the understanding of its close link with the disruption of autophagy mechanisms in the last few years permits the elaboration of new animal models mimicking, through multiple pathways, different aspects of autophagic dysregulation, with the presence of pathological hallmarks, in brain regions affected by Parkinson's disease. The synergic advances in these fields permit the elaboration of multiple therapeutic strategies for restoring autophagy activity. This review discusses the features of Parkinson's disease, the autophagy mechanisms and their involvement in pathogenesis, and the current methods to correct this cellular pathway, from the development of animal models to the potentially curative treatments in the preclinical and clinical phase studies, which are the hope for patients who do not currently have any curative treatment. [ABSTRACT FROM AUTHOR]

Leucine rich-repeat kinase 2 (LRRK2) is the most well-known etiologic gene for familial Parkinson's disease (PD). Its gene product is a large kinase with multiple functional domains that phosphorylates a subset of Rab small GTPases. However, studies of autopsy cases with LRRK2 mutations indicate a varied pathology, and the molecular functions of LRRK2 and its relationship to PD pathogenesis are largely unknown. Recently, non-autonomous neurodegeneration associated with glial cell dysfunction has attracted attention as a possible mechanism of dopaminergic neurodegeneration. Molecular studies of LRRK2 in astrocytes and microglia have also suggested that LRRK2 is involved in the regulation of lysosomal and other organelle dynamics and inflammation. In this review, we describe the proposed functions of LRRK2 in glial cells and discuss its involvement in the pathomechanisms of PD. [ABSTRACT FROM AUTHOR]

In patients affected by Parkinson's disease (PD), the most common neurodegenerative movement disorder, the brain is characterized by the loss of dopaminergic neurons in the nigrostriatal system, leading to dyshomeostasis of the basal ganglia network activity that is linked to motility dysfunction. PD mostly arises as an age-associated sporadic disease, but several genetic forms also exist. Compelling evidence supports that synaptic damage and dysfunction characterize the very early phases of either sporadic or genetic forms of PD and that this early PD synaptopathy drives retrograde terminal-to-cell body degeneration, culminating in neuronal loss. The Ras-associated binding protein (Rab) family of small GTPases, which is involved in the maintenance of neuronal vesicular trafficking, synaptic architecture and function in the central nervous system, has recently emerged among the major players in PD synaptopathy. In this manuscript, we provide an overview of the main findings supporting the involvement of Rabs in either sporadic or genetic PD pathophysiology, and we highlight how Rab alterations participate in the onset of early synaptic damage and dysfunction. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) and other chronic and debilitating neurodegenerative diseases (NDs) impose a substantial medical, emotional, and financial burden on individuals and society. The origin of PD is unknown due to a complex combination of hereditary and environmental risk factors. However, over the last several decades, a significant amount of available data from clinical and experimental studies has implicated neuroinflammation, oxidative stress, dysregulated protein degradation, and mitochondrial dysfunction as the primary causes of PD neurodegeneration. The new gene-editing techniques hold great promise for research and therapy of NDs, such as PD, for which there are currently no effective disease-modifying treatments. As a result, gene therapy may offer new treatment options, transforming our ability to treat this disease. We present a detailed overview of novel gene-editing delivery vehicles, which is essential for their successful implementation in both cutting-edge research and prospective therapeutics. Moreover, we review the most recent advancements in CRISPR-based applications and gene therapies for a better understanding of treating PD. We explore the benefits and drawbacks of using them for a range of gene-editing applications in the brain, emphasizing some fascinating possibilities. [ABSTRACT FROM AUTHOR]

Psychosis in Parkinson's disease (PDP) represents a common and debilitating condition that complicates Parkinson's disease (PD), mainly in the later stages. The spectrum of psychotic symptoms are heterogeneous, ranging from minor phenomena of mild illusions, passage hallucinations and sense of presence to severe psychosis consisting of visual hallucinations (and rarely, auditory and tactile or gustatory) and paranoid delusions. PDP is associated with increased caregiver stress, poorer quality of life for patients and carers, reduced survival and risk of institutionalization with a significant burden on the healthcare system. Although several risk factors for PDP development have been identified, such as aging, sleep disturbances, long history of PD, cognitive impairment, depression and visual disorders, the pathophysiology of psychosis in PD is complex and still insufficiently clarified. Additionally, several drugs used to treat PD can aggravate or even precipitate PDP. Herein, we reviewed and critically analyzed recent studies exploring the genetic architecture of psychosis in PD in order to further understand the pathophysiology of PDP, the risk factors as well as the most suitable therapeutic strategies. [ABSTRACT FROM AUTHOR]

Parkinson's disease may be caused by a single pathogenic variant (monogenic) in 5–10% of cases, but investigation of these disorders provides valuable pathophysiological insights. In this review, we discuss each genetic form with a focus on genotype, phenotype, pathophysiology, and the geographic and ethnic distribution. Well-established Parkinson's disease genes include autosomal dominant forms (SNCA, LRRK2, and VPS35) and autosomal recessive forms (PRKN, PINK1 and DJ1). Furthermore, mutations in the GBA gene are a key risk factor for Parkinson's disease, and there have been major developments for X-linked dystonia parkinsonism. Moreover, atypical or complex parkinsonism may be due to mutations in genes such as ATP13A2, DCTN1, DNAJC6, FBXO7, PLA2G6, and SYNJ1. Furthermore, numerous genes have recently been implicated in Parkinson's disease, such as CHCHD2, LRP10, TMEM230, UQCRC1, and VPS13C. Additionally, we discuss the role of heterozygous mutations in autosomal recessive genes, the effect of having mutations in two Parkinson's disease genes, the outcome of deep brain stimulation, and the role of genetic testing. We highlight that monogenic Parkinson's disease is influenced by ethnicity and geographical differences, reinforcing the need for global efforts to pool large numbers of patients and identify novel candidate genes. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is the second most frequent neurodegenerative disease. It is characterized by the loss of dopaminergic neurons in the substantia nigra and the formation of large aggregates in the survival neurons called Lewy bodies, which mainly contain α-synuclein (α-syn). The cause of cell death is not known but could be due to mitochondrial dysfunction, protein homeostasis failure, and alterations in the secretory/endolysosomal/autophagic pathways. Survival nigral neurons overexpress the small GTPase Rab1. This protein is considered a housekeeping Rab that is necessary to support the secretory pathway, the maintenance of the Golgi complex structure, and the regulation of macroautophagy from yeast to humans. It is also involved in signaling, carcinogenesis, and infection for some pathogens. It has been shown that it is directly linked to the pathogenesis of PD and other neurodegenerative diseases. It has a protective effect against α–σψν toxicity and has recently been shown to be a substrate of LRRK2, which is the most common cause of familial PD and the risk of sporadic disease. In this review, we analyze the key aspects of Rab1 function in dopamine neurons and its implications in PD neurodegeneration/restauration. The results of the current and former research support the notion that this GTPase is a good candidate for therapeutic strategies. [ABSTRACT FROM AUTHOR]

Lewy body disorders (LBD) include Parkinson's disease (PD) and dementia with Lewy bodies (DLB). They are synucleinopathies with a heterogeneous clinical manifestation. As a cause of neuropathological overlap with other neurodegenerative diseases, the establishment of a correct clinical diagnosis is still challenging, and clinical management may be difficult. The combination of genetic variation and epigenetic changes comprising gene expression-modulating DNA methylation and histone alterations modifies the phenotype, disease course, and susceptibility to disease. In this review, we summarize the results achieved in the deciphering of the LBD epigenome. To provide an appropriate context, first LBD genetics is briefly outlined. Afterwards, a detailed review of epigenetic modifications identified for LBD in human cells, postmortem, and peripheral tissues is provided. We also focus on the difficulty of identifying epigenome-related biomarker candidates and discuss the results obtained so far. Additionally, epigenetic changes as therapeutic targets, as well as different epigenome-based treatments, are revised. The number of studies focusing on PD is relatively limited and practically inexistent for DLB. There is a lack of replication studies, and some results are even contradictory, probably due to differences in sample collection and analytical techniques. In summary, we show the current achievements and directions for future research. [ABSTRACT FROM AUTHOR]

Mutations in the protein DJ-1 cause autosomal recessive forms of Parkinson's disease (PD) and oxidized DJ-1 is found in the brains of idiopathic PD individuals. While several functions have been ascribed to DJ-1 (most notably protection from oxidative stress), its contribution to PD pathogenesis is not yet clear. Here we provide an overview of the clinical research to date on DJ-1 and the current state of knowledge regarding DJ-1 characterization in the human brain. The relevance of DJ-1 as a PD biomarker is also discussed, as are studies exploring DJ-1 as a possible therapeutic target for PD and neurodegeneration. [ABSTRACT FROM AUTHOR]