Immunization with α‐synuclein/Grp94 reshapes peripheral immunity and suppresses microgliosis in a chronic Parkinsonism model

Neuroinflammation mediated by chronically activated microglia, largely caused by abnormal accumulation of misfolded α‐synuclein (αSyn) protein, is known to contribute to the pathophysiology of Parkinson's disease (PD). In this work, based on the immunomodulatory activities displayed by particular heat‐shock proteins (HSPs), we tested a novel vaccination strategy that used a combination of αSyn and Grp94 (HSPC4 or Gp96) chaperone and a murine PD model. We used two different procedures, first, the adoptive transfer of splenocytes from αSyn/Grp94‐immunized mice to recipient animals, and second, direct immunization with αSyn/Grp94, to study the effects in a chronic mouse MPTP‐model of parkinsonism. We found that both approaches promoted a distinct profile in the peripheral system—supported by humoral and cellular immunity—consisting of a Th1‐shifted αSyn‐specific response accompanied by an immune‐regulatory/Th2‐skewed general phenotype. Remarkably, this mixed profile sustained by αSyn/Grp94 immunization led to strong suppression of microglial activation in the substantia nigra and striatum, pointing to a newly described positive effect of anti‐αSyn Th1‐responses in the context of PD. This strategy is the first to target αSyn and report the suppression of PD‐associated microgliosis. Overall, we show that the αSyn/Grp94 combination supports a distinct and long‐lasting immune profile in the peripheral system, which has an impact at the CNS level by suppressing chronic microglial activation in an MPTP model of PD. Furthermore, our study demonstrates that reshaping peripheral immunity by vaccination with appropriate misfolding protein/HSP combinations could be highly beneficial as a treatment for neurodegenerative misfolding diseases.     

Lewy body‐related α‐synucleinopathy in the spinal cord of cases with incidental Lewy body disease

Incidental Lewy body disease (ILBD) represents the early asymptomatic phase of Lewy body diseases (LBD), including idiopathic Parkinson's disease (PD). Although pathological disturbances in the spinal cord, which connects the brain to the peripheral nervous system, plays an important role, the pathology of ILBD has not been adequately examined. Eighteen ILBD and eight age‐matched LBD cases were enrolled in the present study. LB‐related pathology was immunohistochemically evaluated using anti‐phosphorylated α‐synuclein (pαSyn) antibodies, revealing LB‐related pathology in the spinal cords of 15 (83.3%) of the ILBD cases. Attempts were made to identify the early pattern of pαSyn deposition in the spinal cord by comparing the cervical, thoracic, lumbar and sacral segments in detail. Most pαSyn‐positive structures were distributed in and around the autonomic nuclei of the spinal cord. The intermediolateral nuclei in the thoracic segments (Th/IML) were the most frequently and severely affected region, suggesting that Th/IML are the first structures affected. Furthermore, following analysis of the distribution pattern of the pαSyn‐positive structures, it is suspected that LB‐related pathology progresses toward the caudal vertebrae by involving neurons in the spinal cord that are vulnerable to αSyn. It should be noted that the ILBD cases enrolled in the present study were in an earlier stage than the PD cases enrolled in the previous study, and that the present study provides new, previously undescribed information.     

From yeast to patient neurons and back again: Powerful new discovery platforms

No disease‐modifying therapies are available for synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple systems atrophy (MSA). The lack of therapies has been impeded by a paucity of validated drug targets and problematic cell‐based model systems. New approaches are therefore needed to identify genes and compounds that directly target the underlying cellular pathologies elicited by the pathological protein, α?synuclein (α?syn). This small, lipid‐binding protein impinges on evolutionarily conserved processes such as vesicle trafficking and mitochondrial function. For decades, the genetically tractable, single‐cell eukaryote, budding yeast, has been used to study nearly all aspects of cell biology. More recently, yeast has revealed key insights into the underlying cellular pathologies caused by α?syn. The robust cellular toxicity caused by α?syn expression facilitates unbiased high‐throughput small‐molecule screening. Critically, one must validate the discoveries made in yeast in disease‐relevant neuronal models. Here, we describe two recent reports that together establish yeast‐to‐human discovery platforms for synucleinopathies. In this exemplar, genes and small molecules identified in yeast were validated in patient‐derived neurons that present the same cellular phenotypes initially discovered in yeast. On validation, we returned to yeast, where unparalleled genetic approaches facilitated the elucidation of a small molecule's mode of action. This approach enabled the identification and neuronal validation of a previously unknown “druggable” node that interfaces with the underlying, precipitating pathologies caused by α?syn. Such platforms can provide sorely needed leads and fresh ideas for disease‐modifying therapy for these devastating diseases. © 2014 International Parkinson and Movement Disorder Society     

Neuropathology of sporadic Parkinson's disease: evaluation and changes of concepts

Parkinson's disease (PD), one of the most frequent neurodegenerative disorders, is no longer considered a complex motor disorder characterized by extrapyramidal symptoms, but a progressive multisystem or-more correctly-multiorgan disease with variegated neurological and nonmotor deficiencies. It is morphologically featured not only by the degeneration of the dopaminergic nigrostriatal system, responsible for the core motor deficits, but by multifocal involvement of the central, peripheral and autonomic nervous system and other organs associated with widespread occurrence of Lewy bodies and dystrophic Lewy neurites. This results from deposition of abnormal α-synuclein (αSyn), the major protein marker of PD, and other synucleinopathies. Recent research has improved both the clinical and neuropathological diagnostic criteria of PD; it has further provided insights into the development and staging of αSyn and Lewy pathologies and has been useful in understanding the pathogenesis of PD. However, many challenges remain, for example, the role of Lewy bodies and the neurobiology of axons in the course of neurodegeneration, the relation between αSyn, Lewy pathology, and clinical deficits, as well as the interaction between αSyn and other pathologic proteins. Although genetic and experimental models have contributed to exploring the causes, pathomechanisms, and treatment options of PD, there is still a lack of an optimal animal model, and the etiology of this devastating disease is far from being elucidated.     

Oxidative stress-induced posttranslational modifications of alpha-synuclein: Specific modification of alpha-synuclein by 4-hydroxy-2-nonenal increases dopaminergic toxicity

Aggregation and neurotoxicity of misfolded alpha-synuclein (αSyn) are crucial mechanisms for progressive dopaminergic neurodegeneration associated with Parkinson's disease (PD). Posttranslational modifications (PTMs) of αSyn caused by oxidative stress, including modification by 4-hydroxy-2-nonenal (HNE-αSyn), nitration (n-αSyn), and oxidation (o-αSyn), have been implicated to promote oligomerization of αSyn. However, it is yet unclear if these PTMs lead to different types of oligomeric intermediates. Moreover, little is known about which PTM-derived αSyn species exerts toxicity to dopaminergic cells. In this study, we directly compared aggregation characteristics of HNE-αSyn, n-αSyn, and o-αSyn. Generally, all of them promoted αSyn oligomerization. Particularly, HNE-αSyn and n-αSyn were more prone to forming oligomers than unmodified αSyn. Moreover, these PTMs prevented the formation of amyloid-like fibrils, although HNE-αSyn and o-αSyn were able to generate protofibrillar structures. The cellular effects associated with distinct PTMs were studied by exposing modified αSyn to dopaminergic Lund human mesencephalic (LUHMES) neurons. The cellular toxicity of HNE-αSyn was significantly higher than other PTM species. Furthermore, we tested the toxicity of HNE-αSyn in dopaminergic LUHMES cells and other cell types with low tyrosine hydroxylase (TH) expression, and additionally analyzed the loss of TH-immunoreactive cells in HNE-αSyn-treated LUHMES cells. We observed a selective toxicity of HNE-αSyn to neurons with higher TH expression. Further mechanistic studies showed that HNE-modification apparently increased the interaction of extracellular αSyn with neurons. Moreover, exposure of differentiated LUHMES cells to HNE-αSyn triggered the production of intracellular reactive oxygen species, preceding neuronal cell death. Antioxidant treatment effectively protected cells from the damage triggered by HNE-αSyn. Our findings suggest a specific pathological effect of HNE-αSyn on dopaminergic neurons.     

Alpha‐synuclein overexpression in mice alters synaptic communication in the corticostriatal pathway

α‐Synuclein (α‐Syn) is a presynaptic protein implicated in Parkinson's disease (PD). Mice overexpressing human wildtype (WT) α‐Syn under the Thy1 promoter show high levels of α‐Syn in cortical and subcortical regions, exhibit progressive sensorimotor anomalies, as well as non‐motor abnormalities and are considered models of pre‐manifest PD as there is little evidence of early loss of dopaminergic (DA) neurons. We used whole‐cell patch clamp recordings from visually identified striatal medium‐sized spiny neurons (MSSNs) in slices from α‐Syn and WT littermate control mice at 35, 90 and 300 days of age to examine corticostriatal synaptic function. MSSNs displayed significant decreases in the frequency of spontaneous excitatory postsynaptic currents (EPSCs) in α‐Syn mice at all ages. This difference persisted in the presence of tetrodotoxin, indicating it was independent of action potentials. Stimulation thresholds for evoking EPSCs were significantly higher and responses were smaller in α‐Syn mice. These data suggest a decrease in neurotransmitter release at the corticostriatal synapse. At 90 days the frequency of spontaneous GABA_A receptor‐mediated synaptic currents was decreased in MSSNs but increased in cortical pyramidal neurons. These observations indicate that high levels of expression of α‐Syn alter corticostriatal synaptic function early and they provide evidence for early synaptic dysfunction in a pre‐manifest model of PD. Of importance, these changes are opposite to those found in DA‐depletion models, suggesting that before degeneration of DA neurons in the substantia nigra synaptic adaptations occur at the corticostriatal synapse that may initiate subtle preclinical manifestations. © 2009 Wiley‐Liss, Inc.     

α‐Synuclein abnormalities in mouse models of peroxisome biogenesis disorders

α‐Synuclein (αS) is a presynaptic protein implicated in Parkinson's disease (PD). Growing evidence implicates mitochondrial dysfunction, oxidative stress, and αS–lipid interactions in the gradual accumulation of αS in pathogenic forms and its deposition in Lewy bodies, the pathological hallmark of PD and related synucleinopathies. The peroxisomal biogenesis disorders (PBD), with Zellweger syndrome serving as the prototype of this group, are characterized by malformed and functionally impaired peroxisomes. Here we utilized the PBD mouse models Pex2–/–, Pex5–/–, and Pex13–/– to study the potential effects of peroxisomal dysfunction on αS‐related pathogenesis. We found increased αS oligomerization and phosphorylation and its increased deposition in cytoplasmic inclusions in these PBD mouse models. Furthermore, we show that αS abnormalities correlate with the altered lipid metabolism and, specifically, with accumulation of long chain, n‐6 polyunsaturated fatty acids that occurs in the PBD models. © 2009 Wiley‐Liss, Inc.     

5‐S‐cysteinyldopamine neurotoxicity: Influence on the expression of α‐synuclein and ERp57 in cellular and animal models of Parkinson's disease

Parkinson's disease (PD) is a progressive neurodegenerative disorder whose etiology is still unclear in spite of extensive investigations. It has been hypothesized that 5‐S‐cysteinyldopamine (CysDA), a catechol‐thioether metabolite of dopamine (DA), could be an endogenous parkinsonian neurotoxin. To gain further insight into its role in the neurodegenerative process, both CD1 mice and SH‐SY5Y neuroblastoma cells were treated with CysDA, and the data were compared with those obtained by the use of 6‐hydroxydopamine, a well‐known parkinsonian mimetic. Intrastriatal injection of CysDA in CD1 mice caused a long‐lasting depletion of DA, providing evidence of in vivo neurotoxicity of CysDA. Both in mice and in SH‐SY5Y cells, CysDA treatment induced extensive oxidative stress, as evidenced by protein carbonylation and glutathione depletion, and affected the expression of two proteins, α‐synuclein (α‐Syn) and ERp57, whose levels are modulated by oxidative insult. Real‐time PCR experiments support these findings, indicating an upregulation of both ERp57 and α‐Syn expression. α‐Syn aggregation was also found to be modulated by CysDA treatment. The present work provides a solid background sustaining the hypothesis that CysDA is involved in parkinsonian neurodegeneration by inducing extensive oxidative stress and protein aggregation. © 2013 Wiley Periodicals, Inc.     

Review: Novel treatment strategies targeting alpha‐synuclein in multiple system atrophy as a model of synucleinopathy

Neurodegenerative disorders with alpha‐synuclein (α‐syn) accumulation (synucleinopathies) include Parkinson's disease (PD), PD dementia, dementia with Lewy bodies and multiple system atrophy (MSA). Due to the involvement of toxic α‐syn aggregates in the molecular origin of these disorders, developing effective therapies targeting α‐syn is a priority as a disease‐modifying alternative to current symptomatic treatments. Importantly, the clinical and pathological attributes of MSA make this disorder an excellent candidate as a synucleinopathy model for accelerated drug development. Recent therapeutic strategies targeting α‐syn in in vivo and in vitro models of MSA, as well as in clinical trials, have been focused on the pathological mechanisms of α‐syn synthesis, aggregation, clearance, and/or cell‐to‐cell propagation of its neurotoxic conformers. Here we summarize the most relevant approaches in this direction, with emphasis on their potential as general synucleinopathy modifiers, and enumerate research areas for potential improvement in MSA drug discovery.     

Engineering synucleinopathy‐resistant human dopaminergic neurons by CRISPR‐mediated deletion of the SNCA gene

An emerging treatment for Parkinson's disease (PD) is cell replacement therapy. Authentic midbrain dopaminergic (mDA) neuronal precursors can be differentiated from human embryonic stem cells (hESCs) and human induced pluripotent stem cells (iPSCs). These laboratory‐generated mDA cells have been demonstrated to mature into functional dopaminergic neurons upon transplantation into preclinical models of PD. However, clinical trials with human fetal mesenchephalic cells have shown that cell replacement grafts in PD are susceptible to Lewy body formation suggesting host‐to‐graft transfer of α‐synuclein pathology. Here, we have used CRISPR/Cas9n technology to delete the endogenous SNCA gene, encoding for α‐synuclein, in a clinical‐grade hESC line to generate SNCA^+/? and SNCA^?/? cell lines. These hESC lines were first differentiated into mDA neurons, and then challenged with recombinant α‐synuclein preformed fibrils (PFFs) to seed the formation for Lewy‐like pathology as measured by phosphorylation of serine‐129 of α‐synuclein (pS129‐αSyn). Wild‐type neurons were fully susceptible to the formation of protein aggregates positive for pS129‐αSyn, while SNCA^+/? and SNCA^?/? neurons exhibited significant resistance to the formation of this pathological mark. This work demonstrates that reducing or completely removing SNCA alleles by CRISPR/Cas9n‐mediated gene editing confers a measure of resistance to Lewy pathology.     

A Brain-Penetrant Stearoyl-CoA Desaturase Inhibitor Reverses α-Synuclein Toxicity

Increasing evidence has shown that Parkinson’s disease (PD) impairs midbrain dopaminergic, cortical and other neuronal subtypes in large part due to the build-up of lipid- and vesicle-rich α-synuclein (αSyn) cytotoxic inclusions. We previously identified stearoyl-CoA desaturase (SCD) as a potential therapeutic target for synucleinopathies. A brain-penetrant SCD inhibitor, YTX-7739, was developed and has entered Phase 1 clinical trials. Here, we report the efficacy of YTX-7739 in reversing pathological αSyn phenotypes in various in vitro and in vivo PD models. In cell-based assays, YTX-7739 decreased αSyn-mediated neuronal death, reversed the abnormal membrane interaction of amplified E46K (“3K”) αSyn, and prevented pathological phenotypes in A53T and αSyn triplication patient-derived neurospheres, including dysregulated fatty acid profiles and pS129 αSyn accumulation. In 3K PD-like mice, YTX-7739 crossed the blood–brain barrier, decreased unsaturated fatty acids, and prevented progressive motor deficits. Both YTX-7739 treatment and decreasing SCD activity through deletion of one copy of the SCD1 gene (SKO) restored the physiological αSyn tetramer-to-monomer ratio, dopaminergic integrity, and neuronal survival in 3K αSyn mice. YTX-7739 efficiently reduced pS129 + and PK-resistant αSyn in both human wild-type αSyn and 3K mutant mice similar to the level of 3K-SKO. Together, these data provide further validation of SCD as a PD therapeutic target and YTX-7739 as a clinical candidate for treating human α-synucleinopathies.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-022-01199-7.     

突触蛋白I片段促进α-突触核蛋白的聚集

目的 探讨突触蛋白I(Synapsin I,Syn I)被剪切后形成的C83片段对α-突触核蛋白聚集的影响。方法 在稳定表达α-突触核蛋白的HEK293细胞、小鼠原代神经元以及Tau P301S转基因小鼠体内分别过表达Syn I全长及其C83片段,通过细胞免疫荧光染色、蛋白免疫印迹技术以及免疫组织化学染色的方法观察Syn I全长及其C83片段对α-突触核蛋白磷酸化及聚集的影响。结果 Syn I C83片段促进HEK293细胞中α-突触核蛋白的磷酸化、泛素化以及聚集,并诱导小鼠原代神经元以及Tau P301S转基因小鼠体内α-突触核蛋白的磷酸化和聚集。结论 在细胞和动物模型中Syn I C83片段均可以促进α-突触核蛋白的聚集,这可能是Syn I C83片段导致认知功能障碍的重要原因之一。     

3‐[(2,4‐dimethoxy)benzylidene]‐anabaseine dihydrochloride protects against 6‐hydroxydopamine‐induced parkinsonian neurodegeneration through α7 nicotinic acetylcholine receptor stimulation in rats

To explore a novel therapy against Parkinson's disease through enhancement of α7 nicotinic acetylcholine receptor (nAChR), we evaluated the neuroprotective effects of 3‐[(2,4‐dimethoxy)benzylidene]‐anabaseine dihydrochloride (DMXBA; GTS‐21), a functionally selective α7 nAChR agonist, in a rat 6‐hydroxydopamine (6‐OHDA)‐induced hemiparkinsonian model. Microinjection of 6‐OHDA into the nigrostriatal pathway of rats destroys dopaminergic neurons selectively. DMXBA dose dependently inhibited methamphetamine‐stimulated rotational behavior and dopaminergic neuronal loss induced by 6‐OHDA. The protective effects were abolished by methyllycaconitine citrate salt hydrate, an α7 nAChR antagonist. Immunohistochemical study confirmed abundant α7 nAChR expression in the cytoplasm of dopaminergic neurons. These results indicate that DMXBA prevented 6‐OHDA‐induced dopaminergic neuronal loss through stimulating α7 nAChR in dopaminergic neurons. Injection of 6‐OHDA elevated immunoreactivities to glial markers such as ionized calcium binding adaptor molecule 1, CD68, and glial fibrillary acidic protein in the substantia nigra pars compacta of rats. In contrast, these immunoreactivities were markedly inhibited by comicroinjection of DMXBA. Microglia also expressed α7 nAChR in both resting and activated states. Hence, we hypothesize that DMXBA simultaneously affects microglia and dopaminergic neurons and that both actions lead to dopaminergic neuroprotection. The findings that DMXBA attenuates 6‐OHDA‐induced dopaminergic neurodegeneration and glial activation in a rat model of Parkinson's disease raisethe possibility that DMXBA could be a novel therapeutic compound to prevent Parkinson's disease development. © 2012 Wiley Periodicals, Inc.     

Short Review: Investigating ARSACS: models for understanding cerebellar degeneration

Autosomal recessive spastic ataxia of Charlevoix‐Saguenay (ARSACS) is an early‐onset neurodegenerative disease that includes progressive cerebellar dysfunction. ARSACS is caused by an autosomal recessive loss‐of‐function mutation in the SACS gene, which encodes for SACSIN. Although animal models are still necessary to investigate the role of SACSIN in the pathology of this disease, more reliable human cellular models need to be generated to better understand the cerebellar pathophysiology of ARSACS. The discovery of human induced pluripotent stem cells (hiPSC) has permitted the derivation of patient‐specific cells. These cells have an unlimited self‐renewing capacity and the ability to differentiate into different neural cell types, allowing studies of disease mechanism, drug discovery and cell replacement therapies. In this study, we discuss how the hiPSC‐derived cerebellar organoid culture offers novel strategies for targeting the pathogenic mutations related to ARSACS. We also highlight the advantages and challenges of this 3D cellular model, as well as the questions that still remain unanswered.     

Alpha-synuclein synaptic pathology and its implications in the development of novel therapeutic approaches to cure Parkinson's disease

Parkinson's disease (PD) is characterized by a progressive loss of dopamine (DA) neurons of the nigrostriatal system and by the presence of Lewy bodies (LB), proteinaceous inclusions mainly composed of filamentous α-synuclein aggregates. Alpha-synuclein is a natively unfolded protein which plays a central role in the control of dopaminergic neuronal functions and which is thought to be critically implicated in PD pathophysiology. Indeed, besides the fact that α-synuclein is the main protein component of LB, genetic studies showed that mutations and multiplications of the α-synuclein gene are responsible for the onset of familial forms of PD. A large body of evidence indicates that α-synuclein pathology at dopaminergic synapses may underlie the onset of neuronal cell dysfunction and degeneration in the PD brain. Thus, since the available therapeutic approaches to cure this disease are still limited, we hypothesized that the analysis of the α-synuclein synaptic proteome/lipidome may represent a tool to identify novel potential therapeutic targets to cure this disorder. We thus performed a critical review of studies describing α-synuclein pathophysiology at synaptic sites in experimental models of PD and in this paper we outline the most relevant findings regarding the specific modulatory effects exerted by α-synuclein in the control of synaptic functions in physiological and pathological conditions. The conclusions of these studies allow to single out novel potential therapeutic targets among the α-synuclein synaptic partners. These targets may be considered for the development of new pharmacological and gene-based strategies to cure PD.     

New Developments in Genetic rat models of Parkinson's Disease

Preclinical research on Parkinson's disease has relied heavily on mouse and rat animal models. Initially, PD animal models were generated primarily by chemical neurotoxins that induce acute loss of dopaminergic neurons in the substantia nigra. On the discovery of genetic mutations causally linked to PD, mice were used more than rats to generate laboratory animals bearing PD‐linked mutations because mutagenesis was more difficult in rats. Recent advances in technology for mammalian genome engineering and optimization of viral expression vectors have increased the use of genetic rat models of PD. Emerging research tools include “knockout” rats with disruption of genes in which mutations have been causally linked to PD, including LRRK2, α‐synuclein, Parkin, PINK1, and DJ‐1. Rats have also been increasingly used for transgenic and viral‐mediated overexpression of genes relevant to PD, particularly α‐synuclein. It may not be realistic to obtain a single animal model that completely reproduces every feature of a human disease as complex as PD. Nevertheless, compared with mice with the same mutations, many genetic rat animal models of PD better reproduce key aspects of PD including progressive loss of dopaminergic neurons in the substantia nigra, locomotor behavior deficits, and age‐dependent formation of abnormal α‐synuclein protein aggregates. Here we briefly review new developments in genetic rat models of PD that may have greater potential for identifying underlying mechanisms, for discovering novel therapeutic targets, and for developing greatly needed treatments to slow or halt disease progression. © 2018 International Parkinson and Movement Disorder Society     

Interaction between α-synuclein and tau in Parkinson's disease comment on Wills et al.: elevated tauopathy and α-synuclein pathology in postmortem Parkinson's disease brains with and without dementia. Exp Neurol 2010; 225: 210-218

Recent neurochemical studies in postmortem brains of patients with Parkinson's disease (PD), PD with dementia (PDD) and age-matched controls revealed significant decrease of tyrosine hydroxylase (TH) and dopamine transporter (DAT) in striatum, confirming previous studies indicating substantial loss of dopaminergic neurons and terminals. Insoluble α-synuclein (αSyn) was significantly increased in both striata and inferior frontal gyrus (IFG), more severe in PDD, probably related to Lewy body (LB) burden discussed as one cause of dementia in PD. Parkin levels frequently related to recessive and young-onset PD were unchanged, suggesting no link to sporadic PD. Novel and most interesting data showed elevated tauopathy in striata of both PD and PDD, associated with increased levels of phosphorylated GSK-3β and reduced 20S proteasomal subunits but – despite increased cortical αSyn – unchanged pTau in IFG, related to increased pGSK-3β and decreased 19S proteasome subunits. These data, recently confirmed in PDGF-αSyn transgenic mice (Haggerty et al., submitted) suggest tauopathy in PD and PDD restricted to the dopaminergic nigrostriatal system and in various animal models of PD show topographic differences from a global tauopathy in Alzheimer's disease (AD) (and other tauopathies). Although some of these data are at variance to current neuropathologic findings in PD and PDD, they confirm frequently discussed correlations/overlaps between AD and PD/PDD and synergistic effects of αSyn, pTau, β-amyloid, and other pathologic proteins, suggesting a dualism or triad of neurodegeneration, the basic molecular pathogenesis remains to be elucidated.     

Overcoming obstacles in Parkinson's disease

Improved symptomatic and disease‐modifying treatments are needed for Parkinson's disease (PD). Although significant advances have been made in the understanding of PD etiology, the translation of these discoveries into novel transformative therapies has been limited as a result of systemic challenges in PD drug development. Preclinical testing lacks clear standards and prioritization criteria for advancing therapies to the clinic. Clinical testing is marked by expensive, long, and uninformative studies. In parallel to these scientific challenges, funding of late‐stage drug development has become increasingly scarce and risk averse. In this context, novel models of collaboration and funding are opening up new avenues for pursuing treatments. This review will discuss the most critical challenges in PD drug development and the innovative approaches being developed to overcome these hurdles. © 2012 Movement Disorder Society     

α-Synuclein decoy peptide protects mice against α-synuclein-induced memory loss

Aims

We previously found that a decoy peptide derived from the C-terminal sequence of α-Synuclein (αSyn) prevents cytotoxic αSyn aggregation caused by fatty acid-binding protein 3 (FABP3) in vitro. In this study, we continued to utilize αSyn-derived peptides to further validate their effects on αSyn neurotoxicity and behavioral impairments in αSyn preformed fibrils (PFFs)-injected mouse model of Parkinson's disease (PD).

Methods

Mice were injected with αSyn PFFs in the bilateral olfactory bulb (OB) and then were subjected to behavioral analysis at 2-week intervals post-injection. Peptides nasal administration was initiated one week after injection. Changes in phosphorylation of αSyn and neuronal damage in the OB were measured using immunostaining at week 4. The effect of peptides on the interaction between αSyn and FABP3 was examined using co-immunoprecipitation.

Results

αSyn PFF-injected mice showed significant memory loss but no motor function impairment. Long-term nasal treatment with peptides effectively prevented memory impairment. In peptide-treated αSyn PFF-injected mice, the peptides entered the OB smoothly through the nasal cavity and were mainly concentrated in neurons in the mitral cell layer, significantly suppressing the excessive phosphorylation of αSyn and reducing the formation of αSyn-FABP3 oligomers, thereby preventing neuronal death. The addition of peptides also blocked the interaction of αSyn and FABP3 at the recombinant protein level, and its effect was strongest at molar concentrations comparable to those of αSyn and FABP3.

Conclusions

Our findings suggest that the αSyn decoy peptide represents a novel therapeutic approach for reducing the accumulation of toxic αSyn-FABP3 oligomers in the brain, thereby preventing the progression of synucleinopathies.