scholarly journals Alpha-Synuclein and LRRK2 in Synaptic Autophagy: Linking Early Dysfunction to Late-Stage Pathology in Parkinson’s Disease

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1115 ◽  
Author(s):  
Giulia Lamonaca ◽  
Mattia Volta
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Late Stage ◽  
Disease Onset ◽  
Disease Process ◽  
Alpha Synuclein ◽  
Synaptic Activity ◽  
Early Event ◽  
Cellular Targets ◽  
Disease Modifying

The lack of effective disease-modifying strategies is the major unmet clinical need in Parkinson’s disease. Several experimental approaches have attempted to validate cellular targets and processes. Of these, autophagy has received considerable attention in the last 20 years due to its involvement in the clearance of pathologic protein aggregates and maintenance of neuronal homeostasis. However, this strategy mainly addresses a very late stage of the disease, when neuropathology and neurodegeneration have likely “tipped over the edge” and disease modification is extremely difficult. Very recently, autophagy has been demonstrated to modulate synaptic activity, a process distinct from its catabolic function. Abnormalities in synaptic transmission are an early event in neurodegeneration with Leucine-Rich Repeat Kinase 2 (LRRK2) and alpha-synuclein strongly implicated. In this review, we analyzed these processes separately and then discussed the unification of these biomolecular fields with the aim of reconstructing a potential “molecular timeline” of disease onset and progression. We postulate that the elucidation of these pathogenic mechanisms will form a critical basis for the design of novel, effective disease-modifying therapies that could be applied early in the disease process.

scholarly journals Alpha-synuclein antisense oligonucleotides as a disease-modifying therapy for Parkinson’s disease

2019 ◽  
Author(s):  
Tracy A. Cole ◽  
Hien Zhao ◽  
Timothy J. Collier ◽  
Ivette Sandoval ◽  
Caryl E. Sortwell ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Antisense Oligonucleotides ◽  
Alpha Synuclein ◽  
Nucleotide Polymorphisms ◽  
Gene Encoding ◽  
Disease Modifying Therapy ◽  
Increase Risk ◽  
Disease Modifying

AbstractParkinson’s disease (PD) is a prevalent neurodegenerative disease with no approved disease-modifying therapies. Multiplications, mutations, and single nucleotide polymorphisms in the SNCA gene, encoding alpha-synuclein protein (aSyn), either cause or increase risk for PD. Intracellular accumulations of aSyn are pathological hallmarks of PD. Taken together, reduction of aSyn production may provide a disease-modifying therapy for PD. We show that antisense oligonucleotides (ASOs) reduce production of aSyn in rodent pre-formed fibril (PFF) models of PD. Reduced aSyn production leads to prevention and removal of established aSyn pathology and prevents dopaminergic cell dysfunction. In addition, we address the translational potential of the approach through characterization of human SNCA targeting ASOs that efficiently suppress the human SNCA transcript in vivo. We demonstrate broad activity and distribution of the human SNCA ASOs throughout the non-human primate brain and a corresponding decrease in aSyn cerebral spinal fluid (CSF) levels. Taken together, these data suggest that by inhibiting production of aSyn it may be possible to reverse established pathology and thus supports the development of SNCA ASOs as a potentially disease modifying therapy for PD and related synucleinopathies.SummaryAntisense oligonucleotides designed against SNCA, which are progressing to the clinic, have the potential to be a disease modifying therapeutic for Parkinson’s disease patients.

scholarly journals Olfaction and Colour Vision: What Can They Tell Us about Parkinson’s Disease?

2018 ◽  
Vol 119 (2-3) ◽  
pp. 85-96 ◽  
Author(s):  
Irene Dall’Antonia ◽  
Karel Šonka ◽  
Petr Dušek
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Colour Vision ◽  
Neurodegenerative Disorder ◽  
Disease Onset ◽  
Alpha Synuclein ◽  
Nerve Tissue ◽  
Clinical Markers ◽  
Motor Abnormalities ◽  
Non Motor Symptoms

Parkinson’s disease is a neurodegenerative disorder with the pathological accumulation of alpha synuclein in the brain and peripheral nerve tissue. Early stages of synucleinopathies, often present clinically with rapid eye movement (REM) sleep disorder (RBD). Clinical markers that indicate early progression from RBD to manifest synucleinopathies include abnormal dopamine transporter (DAT) imaging, motor and non-motor symptoms. Despite the high diagnostic strength of DAT imaging and motor abnormalities, they are not the earliest biomarkers. Non-motor signs of neurodegeneration such as colour vision and olfaction abnormalities are detectable by clinical examination as early as 20 years before disease onset. Detailed analysis of olfactory and colour vision dysfunction can provide valuable information regarding brain pathologies, further specifying clinical phenotypes, and giving clues to underlying pathophysiological mechanisms in Parkinson’s disease and related disorders.

scholarly journals The Future of Targeted Gene-Based Treatment Strategies and Biomarkers in Parkinson’s Disease

Biomolecules ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 912 ◽  
Author(s):  
Alexia Polissidis ◽  
Lilian Petropoulou-Vathi ◽  
Modestos Nakos-Bimpos ◽  
Hardy J. Rideout
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Treatment Strategies ◽  
Disease Diagnosis ◽  
Alpha Synuclein ◽  
Strategy Development ◽  
Early Detection Of Disease ◽  
Medical Needs ◽  
Disease Modifying Therapies ◽  
Disease Modifying

Biomarkers and disease-modifying therapies are both urgent unmet medical needs in the treatment of Parkinson’s disease (PD) and must be developed concurrently because of their interdependent relationship: biomarkers for the early detection of disease (i.e., prior to overt neurodegeneration) are necessary in order for patients to receive maximal therapeutic benefit and vice versa; disease-modifying therapies must become available for patients whose potential for disease diagnosis and prognosis can be predicted with biomarkers. This review provides an overview of the milestones achieved to date in the therapeutic strategy development of disease-modifying therapies and biomarkers for PD, with a focus on the most common and advanced genetically linked targets alpha-synuclein (SNCA), leucine-rich repeat kinase-2 (LRRK2) and glucocerebrosidase (GBA1). Furthermore, we discuss the convergence of the different pathways and the importance of patient stratification and how these advances may apply more broadly to idiopathic PD. The heterogeneity of PD poses a challenge for therapeutic and biomarker development, however, the one gene- one target approach has brought us closer than ever before to an unprecedented number of clinical trials and biomarker advancements.

scholarly journals Classic and New Animal Models of Parkinson's Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Javier Blesa ◽  
Sudarshan Phani ◽  
Vernice Jackson-Lewis ◽  
Serge Przedborski
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Animal Models ◽  
Molecular Mechanisms ◽  
Behavioral Outcomes ◽  
Disease Process ◽  
Alpha Synuclein ◽  
Cellular Models ◽  
6 Hydroxydopamine ◽  
Almost All

Neurological disorders can be modeled in animals so as to recreate specific pathogenic events and behavioral outcomes. Parkinson’s Disease (PD) is the second most common neurodegenerative disease of an aging population, and although there have been several significant findings about the PD disease process, much of this process still remains a mystery. Breakthroughs in the last two decades using animal models have offered insights into the understanding of the PD disease process, its etiology, pathology, and molecular mechanisms. Furthermore, while cellular models have helped to identify specific events, animal models, both toxic and genetic, have replicated almost all of the hallmarks of PD and are useful for testing new neuroprotective or neurorestorative strategies. Moreover, significant advances in the modeling of additional PD features have come to light in both classic and newer models. In this review, we try to provide an updated summary of the main characteristics of these models as well as the strengths and weaknesses of what we believe to be the most popular PD animal models. These models include those produced by 6-hydroxydopamine (6-OHDA), 1-methyl-1,2,3,6-tetrahydropiridine (MPTP), rotenone, and paraquat, as well as several genetic models like those related to alpha-synuclein, PINK1, Parkin and LRRK2 alterations.

scholarly journals Metformin rescues Parkinson’s disease phenotypes caused by hyperactive mitochondria

2020 ◽  
Vol 117 (42) ◽  
pp. 26438-26447 ◽  
Author(s):  
Danielle E. Mor ◽  
Salman Sohrabi ◽  
Rachel Kaletsky ◽  
William Keyes ◽  
Alp Tartici ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Respiration ◽  
Mammalian Target Of Rapamycin ◽  
Disease Onset ◽  
Motor Deficits ◽  
Early Event ◽  
Disease Etiology ◽  
Neuronal Viability ◽  
Age Related

Metabolic dysfunction occurs in many age-related neurodegenerative diseases, yet its role in disease etiology remains poorly understood. We recently discovered a potential causal link between the branched-chain amino acid transferaseBCAT-1and the neurodegenerative movement disorder Parkinson’s disease (PD). RNAi-mediated knockdown ofCaenorhabditis elegans bcat-1is known to recapitulate PD-like features, including progressive motor deficits and neurodegeneration with age, yet the underlying mechanisms have remained unknown. Using transcriptomic, metabolomic, and imaging approaches, we show here thatbcat-1knockdown increases mitochondrial respiration and induces oxidative damage in neurons through mammalian target of rapamycin-independent mechanisms. Increased mitochondrial respiration, or “mitochondrial hyperactivity,” is required forbcat-1(RNAi)neurotoxicity. Moreover, we show that post–disease-onset administration of the type 2 diabetes medication metformin reduces mitochondrial respiration to control levels and significantly improves both motor function and neuronal viability. Taken together, our findings suggest that mitochondrial hyperactivity may be an early event in the pathogenesis of PD, and that strategies aimed at reducing mitochondrial respiration may constitute a surprising new avenue for PD treatment.

scholarly journals Synucleinopathy-associated pathogenesis in Parkinson’s disease and the potential for brain-derived neurotrophic factor

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Kathryn M. Miller ◽  
Natosha M. Mercado ◽  
Caryl E. Sortwell
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurotrophic Factor ◽  
Lewy Bodies ◽  
Brain Derived Neurotrophic Factor ◽  
Alpha Synuclein ◽  
Comprehensive Overview ◽  
Lewy Pathology ◽  
Disease Modifying

AbstractThe lack of disease-modifying treatments for Parkinson’s disease (PD) is in part due to an incomplete understanding of the disease’s etiology. Alpha-synuclein (α-syn) has become a point of focus in PD due to its connection to both familial and idiopathic cases—specifically its localization to Lewy bodies (LBs), a pathological hallmark of PD. Within this review, we will present a comprehensive overview of the data linking synuclein-associated Lewy pathology with intracellular dysfunction. We first present the alterations in neuronal proteins and transcriptome associated with LBs in postmortem human PD tissue. We next compare these findings to those associated with LB-like inclusions initiated by in vitro exposure to α-syn preformed fibrils (PFFs) and highlight the profound and relatively unique reduction of brain-derived neurotrophic factor (BDNF) in this model. Finally, we discuss the multitude of ways in which BDNF offers the potential to exert disease-modifying effects on the basal ganglia. What remains unknown is the potential for BDNF to mitigate inclusion-associated dysfunction within the context of synucleinopathy. Collectively, this review reiterates the merit of using the PFF model as a tool to understand the physiological changes associated with LBs, while highlighting the neuroprotective potential of harnessing endogenous BDNF.

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