Parkinson's disease or multiple system atrophy: potential separation by quantitative susceptibility mapping.

Background: Due to the absence of robust biomarkers, and the low sensitivity and specificity of routine imaging techniques, the differential diagnosis between Parkinson's disease (PD) and multiple system atrophy (MSA) is challenging. High-field magnetic resonance imaging (MRI) opened up new possibilities regarding the analysis of pathological alterations associated with neurodegenerative processes. Recently, we have shown that quantitative susceptibility mapping (QSM) enables visualization and quantification of two major histopathologic hallmarks observed in MSA: reduced myelin density and iron accumulation in the basal ganglia of a transgenic murine model of MSA. It is therefore emerging as a promising imaging modality on the differential diagnosis of Parkinsonian syndromes. Objectives: To assess QSM on high-field MRI for the differential diagnosis of PD and MSA. Methods: We assessed 23 patients (nine PDs and 14 MSAs) and nine controls using QSM on 3T and 7T MRI scanners at two academic centers. Results: We observed increased susceptibility in MSA at 3T in prototypical subcortical and brainstem regions. Susceptibility measures of putamen, pallidum, and substantia nigra reached excellent diagnostic accuracy to separate both synucleinopathies. Increase toward 100% sensitivity and specificity was achieved using 7T MRI in a subset of patients. Magnetic susceptibility correlated with age in all groups, but not with disease duration in MSA. Sensitivity and specificity were particularly high for possible MSA, and reached 100% in the putamen. Conclusion: Putaminal susceptibility measures, in particular on ultra-high-field MRI, may distinguish MSA patients from both, PD and controls, allowing an early and sensitive diagnosis of MSA.

An alternative splicing modulator decreases mutant HTT and improves the molecular fingerprint in Huntington's disease patient neurons.

Huntington's disease (HD) is a neurodegenerative disorder caused by poly-Q expansion in the Huntingtin (HTT) protein. Here, we delineate elevated mutant HTT (mHTT) levels in patient-derived cells including fibroblasts and iPSC derived cortical neurons using mesoscale discovery (MSD) HTT assays. HD patients' fibroblasts and cortical neurons recapitulate aberrant alternative splicing as a molecular fingerprint of HD. Branaplam is a splicing modulator currently tested in a phase II study in HD (NCT05111249). The drug lowers total HTT (tHTT) and mHTT levels in fibroblasts, iPSC, cortical progenitors, and neurons in a dose dependent manner at an IC50 consistently below 10 nM without inducing cellular toxicity. Branaplam promotes inclusion of non-annotated novel exons. Among these Branaplam-induced exons, there is a 115 bp frameshift-inducing exon in the HTT transcript. This exon is observed upon Branaplam treatment in Ctrl and HD patients leading to a profound reduction of HTT RNA and protein levels. Importantly, Branaplam ameliorates aberrant alternative splicing in HD patients' fibroblasts and cortical neurons. These findings highlight the applicability of splicing modulators in the treatment of CAG repeat disorders and decipher their molecular effects associated with the pharmacokinetic and -dynamic properties in patient-derived cellular models.

Reduced synaptic activity and dysregulated extracellular matrix pathways in midbrain neurons from Parkinson's disease patients.

Several mutations that cause Parkinson's disease (PD) have been identified over the past decade. These account for 15-25% of PD cases; the rest of the cases are considered sporadic. Currently, it is accepted that PD is not a single monolithic disease but rather a constellation of diseases with some common phenotypes. While rodent models exist for some of the PD-causing mutations, research on the sporadic forms of PD is lagging due to a lack of cellular models. In our study, we differentiated PD patient-derived dopaminergic (DA) neurons from the induced pluripotent stem cells (iPSCs) of several PD-causing mutations as well as from sporadic PD patients. Strikingly, we observed a common neurophysiological phenotype: neurons derived from PD patients had a severe reduction in the rate of synaptic currents compared to those derived from healthy controls. While the relationship between mutations in genes such as the SNCA and LRRK2 and a reduction in synaptic transmission has been investigated before, here we show evidence that the pathogenesis of the synapses in neurons is a general phenotype in PD. Analysis of RNA sequencing results displayed changes in gene expression in different synaptic mechanisms as well as other affected pathways such as extracellular matrix-related pathways. Some of these dysregulated pathways are common to all PD patients (monogenic or idiopathic). Our data, therefore, show changes that are central and convergent to PD and suggest a strong involvement of the tetra-partite synapse in PD pathophysiology.

Aberrant NOVA1 function disrupts alternative splicing in early stages of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by aberrant alternative splicing (AS). Nuclear loss and cytoplasmic accumulation of the splicing factor TDP-43 in motor neurons (MN) are hallmarks of ALS at late stages of the disease. However, it is unknown if altered AS is present before TDP-43 pathology occurs. Here, we investigate altered AS and its origins in early stages of ALS using human induced pluripotent stem cell-derived motor neurons (MNs) from sporadic and familial ALS patients. We find high levels of the RNA-binding proteins NOVA1, NOVA2, and RBFOX2 in the insoluble protein fractions and observe that AS events in ALS-associated MNs are enriched for binding sites of these proteins. Our study points to an early disrupted function of NOVA1 that drives AS changes in a complex fashion, including events caused by a consistent loss of NOVA1 function. NOVA1 exhibits increased cytoplasmic protein levels in early stage MNs without TDP-43 pathology in ALS postmortem tissue. As nuclear TDP-43 protein level depletes, NOVA1 is reduced. Potential indications for a reduction of NOVA1 also came from mice over-expressing TDP-43 lacking its nuclear localization signal and iPSC-MN stressed with puromycin. This study highlights that additional RBP-RNA perturbations in ALS occur in parallel to TDP-43.

Life style and Parkinson's disease.

The question whether life style may impair the advent or course of the disease in patients with Parkinsonism is of great importance for patients and physicians alike. We present here comprehensive information on the influence of the environment, diet (especially caffeine, nicotine, alcohol, chocolate and dairy products), physical activity and sleep on risk and course of Parkinson's disease.

[The history of Freezing-of-gait in Parkinson's disease - from phenomena to symptom]. / Die Geschichte des 'Freezing-of-gait' beim Parkinson-Syndrom ­ vom Phänomen zum Symptom.

The background of the freezing-of-gait (FOG) phenomenon in Parkinson's syndrome is presented in this review. The following issues are addressed: characterization of the symptom freezing and its subtypes that challenge standardized diagnostic procedures; available assessment methods generating freezing-related parameters that not only support clinical studies but can also be applied in everyday care, and current therapy options. FOG exists in different subtypes, and clinical and diagnostic definitions are limited by subjective characterization and semi-standardized tests. FOG-specific drug options are not existing, apart from the optimization of dopaminergic medication, which may also be due to the poor discriminatory power of standardized diagnostics. This is also true for deep brain stimulation. Both of these therapeutic options may be due not only to the complex neural network alterations as a motor-control correlate of FOG, but also because of challenging diagnostic assessments methodologies. Innovative, wearable, sensor-based diagnostic strategies are currently being developed, and supportive therapies using tools and technologies focusing on 'cueing' are becoming increasingly well accepted. Even though high level evidence is missing, they provide a helpful treatment option for individualized therapy. It can be assumed that these options will become particularly popular due to technological progress and likely alter the everyday treatment challenges faced by doctors and therapists.

Ascending Axonal Degeneration of the Corticospinal Tract in Pure Hereditary Spastic Paraplegia: A Cross-Sectional DTI Study.

OBJECTIVE: To identify structural white matter alterations in patients with pure hereditary spastic paraplegia (HSP) using high angular resolution diffusion tensor imaging (DTI). METHODS: We examined 37 individuals with high resolution DTI, 20 patients with pure forms of hereditary spastic paraplegia and 17 age and gender matched healthy controls. DTI was performed using a 3 T clinical scanner with whole brain tract-based spatial statistical (TBSS) analysis of the obtained fractional anisotropy (FA) data as well as a region-of-interest (ROI)-based analysis of affected tracts including the cervical spinal cord. We further conducted correlation analyses between DTI data and clinical characteristics. RESULTS: TBSS analysis in HSP patients showed significantly decreased fractional anisotropy of the corpus callosum and the corticospinal tract compared to healthy controls. ROI-based analysis confirmed significantly lower FA in HSP compared to controls in the internal capsule (0.77 vs. 0.80, p = 0.048), the corpus callosum (0.84 vs. 0.87, p = 0.048) and the cervical spinal cord (0.72 vs. 0.79, p = 0.003). FA values of the cervical spinal cord significantly correlated with disease duration. CONCLUSION: DTI metrics of the corticospinal tract from the internal capsule to the cervical spine suggest microstructural damage and axonal degeneration of motor neurons. The CST at the level of the cervical spinal cord is thereby more severely affected than the intracranial part of the CST, suggesting an ascending axonal degeneration of the CST. Since there is a significant correlation with disease duration, FA may serve as a future progression marker for assessment of the disease course in HSP.

Sensor-based gait analysis in atypical parkinsonian disorders.

BACKGROUND AND OBJECTIVES: Gait impairment and reduced mobility are typical features of idiopathic Parkinson's disease (iPD) and atypical parkinsonian disorders (APD). Quantitative gait assessment may have value in the diagnostic workup of parkinsonian patients and as endpoint in clinical trials. The study aimed to identify quantitative gait parameter differences in iPD and APD patients using sensor-based gait analysis and to correlate gait parameters with clinical rating scales. SUBJECTS AND METHODS: Patients with iPD and APD including Parkinson variant multiple system atrophy and progressive supranuclear palsy matched for age, gender, and Hoehn and Yahr (≤3) were recruited at two Movement Disorder Units and assessed using standardized clinical rating scales (MDS-UPDRS-3, UMSARS, PSP-RS). Gait analysis consisted of inertial sensor units laterally attached to shoes, generating as objective targets spatiotemporal gait parameters from 4 × 10 m walk tests. RESULTS: Objective sensor-based gait analysis showed that gait speed and stride length were markedly reduced in APD compared to iPD patients. Moreover, clinical ratings significantly correlated with gait speed and stride length in APD patients. CONCLUSION: Our findings suggest that patients with APD had more severely impaired gait parameters than iPD patients despite similar disease severity. Instrumented gait analysis provides complementary rater independent, quantitative parameters that can be exploited for clinical trials and care.

Ultra high-field SWI of the substantia nigra at 7T: reliability and consistency of the swallow-tail sign.

BACKGROUND: The loss of the swallow-tail sign of the substantia nigra has been proposed for diagnosis of Parkinson's disease. Aim was to evaluate, if the sign occurs consistently in healthy subjects and if it can be reliably detected with high-resolution 7T susceptibility weighted imaging (SWI). METHODS: Thirteen healthy adults received SWI at 7T. 3 neuroradiologists, who were blinded to patients' diagnosis, independently classified subjects regarding the swallow-tail sign to be present or absent. Accuracy, positive and negative predictive values (PPV and NPV) as well as inter- and intra-rater reliability and internal consistency were analyzed. RESULTS: The sign could be detected in 81% of the cases in consensus reading. Accuracy to detect the sign compared to the consensus was 100, 77 and 96% for the three readers with PPV reader 1/2/3 = 1/0.45/0.83 and NPV = 1/1/1. Inter-rater reliability was excellent (inter-class correlation coefficient = 0.844, alpha = 0.871). Intra-rater reliability was good to excellent (reader 1 R/L = 0.625/0.786; reader 2 = 0.7/0.64; reader 3 = 0.9/1). CONCLUSION: The swallow-tail sign can be reliably detected. However, our data suggest its occurrence is not consistent in healthy subjects. It may be possible that one reason is an individually variable molecular organization of nigrosome 1 so that it does not return a uniform signal in SWI.

Acute Neuromuscular Adaptations in the Postural Control of Patients with Parkinson's Disease after Perturbed Walking.

Patients suffering from Parkinson's disease (PD) present motor impairments reflected in the dynamics of the center of pressure (CoP) adjustments during quiet standing. One method to study the dynamics of CoP adjustments is the entropic half-life (EnHL), which measures the short-term correlations of a time series at different time scales. Changes in the EnHL of CoP time series suggest neuromuscular adaptations in the control of posture. In this study, we sought to investigate the immediate changes in the EnHL of CoP adjustments of patients with PD during one session of perturbed (experimental group) and unperturbed treadmill walking (control group). A total of 39 patients with PD participated in this study. The experimental group (n = 19) walked on a treadmill providing small tilting of the treadmill platform. The control group (n = 20) walked without perturbations. Each participant performed 5-min practice followed by three 5-min training blocks of walking with or without perturbation (with 3-min resting in between). Quiet standing CoP data was collected for 30 s at pre-training, after each training block, immediately post-training, and after 10 min retention. The EnHL was computed on the original and surrogates (phase-randomized) CoP signals in the medio-lateral (ML) and anterior-posterior (AP) directions. Data was analyzed using four-way mixed ANOVA. Increased EnHL values were observed for both groups (Time effect, p < 0.001) as the intervention progressed, suggesting neuromuscular adaptations in the control of posture. The EnHL of surrogate signals were significantly lower than for original signals (p < 0.001), confirming that these adaptations come from non-random control processes. There was no Group effect (p = 0.622), however by analyzing the significant Group by Direction by Time interaction (p < 0.05), a more pronounced effect in the ML direction of the perturbed group was observed. Altogether, our findings show that treadmill walking decreases the complexity of CoP adjustments, suggesting neuromuscular adaptations in balance control during a short training period. Further investigations are required to assess these adaptations during longer training intervals.

47 patients with FLNA associated periventricular nodular heterotopia.

BACKGROUND: Heterozygous loss of function mutations within the Filamin A gene in Xq28 are the most frequent cause of bilateral neuronal periventricular nodular heterotopia (PVNH). Most affected females are reported to initially present with difficult to treat seizures at variable age of onset. Psychomotor development and cognition may be normal or mildly to moderately impaired. Distinct associated extracerebral findings have been observed and may help to establish the diagnosis including patent ductus arteriosus Botalli, progressive dystrophic cardiac valve disease and aortic dissection, chronic obstructive lung disease or chronic constipation. Genotype-phenotype correlations could not yet be established. METHODS: Sanger sequencing and MLPA was performed for a large cohort of 47 patients with Filamin A associated PVNH (age range 1 to 65 years). For 34 patients more detailed clinical information was available from a structured questionnaire and medical charts on family history, development, epileptologic findings, neurological examination, cognition and associated clinical findings. Available detailed cerebral MR imaging was assessed for 20 patients. RESULTS: Thirty-nine different FLNA mutations were observed, they are mainly truncating (37/39) and distributed throughout the entire coding region. No obvious correlation between the number and extend of PVNH and the severity of the individual clinical manifestation was observed. 10 of the mutation carriers so far are without seizures at a median age of 19.7 years. 22 of 24 patients with available educational data were able to attend regular school and obtain professional education according to age. CONCLUSIONS: We report the clinical and mutation spectrum as well as MR imaging for a large cohort of 47 patients with Filamin A associated PVNH including two adult males. Our data are reassuring in regard to psychomotor and cognitive development, which is within normal range for the majority of patients. However, a concerning median diagnostic latency of 17 to 20 years was noted between seizure onset and the genetic diagnosis, intensely delaying appropriate medical surveillance for potentially life threatening cardiovascular complications as well as genetic risk assessment and counseling prior to family planning for this X-linked dominant inherited disorder with high perinatal lethality in hemizygous males.

An Emerging Era in the Management of Parkinson's Disease: Wearable Technologies and the Internet of Things.

Current challenges demand a profound restructuration of the global healthcare system. A more efficient system is required to cope with the growing world population and increased life expectancy, which is associated with a marked prevalence of chronic neurological disorders such as Parkinson's disease (PD). One possible approach to meet this demand is a laterally distributed platform such as the Internet of Things (IoT). Real-time motion metrics in PD could be obtained virtually in any scenario by placing lightweight wearable sensors in the patient's clothes and connecting them to a medical database through mobile devices such as cell phones or tablets. Technologies exist to collect huge amounts of patient data not only during regular medical visits but also at home during activities of daily life. These data could be fed into intelligent algorithms to first discriminate relevant threatening conditions, adjust medications based on online obtained physical deficits, and facilitate strategies to modify disease progression. A major impact of this approach lies in its efficiency, by maximizing resources and drastically improving the patient experience. The patient participates actively in disease management via combined objective device- and self-assessment and by sharing information within both medical and peer groups. Here, we review and discuss the existing wearable technologies and the Internet-of-Things concept applied to PD, with an emphasis on how this technological platform may lead to a shift in paradigm in terms of diagnostics and treatment.

Autophagy modulates SNCA/α-synuclein release, thereby generating a hostile microenvironment.

SNCA/α-synuclein aggregation plays a crucial role in synucleinopathies such as Parkinson disease and dementia with Lewy bodies. Aggregating and nonaggregating SNCA species are degraded by the autophagy-lysosomal pathway (ALP). Previously, we have shown that the ALP is not only responsible for SNCA degradation but is also involved in the intracellular aggregation process of SNCA. An additional role of extracellular SNCA in the pathology of synucleinopathies substantiating a prion-like propagation hypothesis has been suggested since released SNCA species and spreading of SNCA pathology throughout neural cells have been observed. However, the molecular interplay between intracellular pathways, SNCA aggregation, release, and response of the local microenvironment remains unknown. Here, we attributed SNCA-induced toxicity mainly to secreted species in a cell culture model of SNCA aggregation and in SNCA transgenic mice: We showed that ALP inhibition by bafilomycinA1 reduced intracellular SNCA aggregation but increased secretion of smaller oligomers that exacerbated microenvironmental response including uptake, inflammation, and cellular damage. Low-aggregated SNCA was predominantly released by exosomes and RAB11A-associated pathways whereas high-aggregated SNCA was secreted by membrane shedding. In summary, our study revealed a novel role of the ALP by linking protein degradation to nonclassical secretion for toxic SNCA species. Thus, impaired ALP in the diseased brain not only limits intracellular degradation of misfolded proteins, but also leads to a detrimental microenvironmental response due to enhanced SNCA secretion. These findings suggest that the major toxic role of SNCA is related to its extracellular species and further supports a protective role of intracellular SNCA aggregation.

Automatic recognition of Parkinson's disease using surface electromyography during standardized gait tests.

Diagnosis and severity staging of Parkinsons disease (PD) relies mainly on subjective clinical examination. To better monitor disease progression and therapy success in PD patients, new objective and rater independent parameters are required. Surface electromyography (EMG) during dynamic movements is one possible modality. However, EMG signals are often difficult to understand and interpret clinically. In this study pattern recognition was applied to find suitable parameters to differentiate PD patients from healthy controls. EMG signals were recorded from 5 patients with PD and 5 younger healthy controls, while performing a series of standardized gait tests. Wireless surface electrodes were placed bilaterally on tibialis anterior and gastrocnemius medialis and lateralis. Accelerometers were positioned on both heels and used for step segmentation. Statistical and frequency features were extracted and used to train a Support Vector Machine classifier. Sensitivity and specificity were high at 0.90 using leave-one-subject-out cross-validation. Feature selection revealed kurtosis and mean frequency as best features, with a significant difference in kurtosis (p=0.013). Evaluated on a bigger population, this could lead to objective diagnostic and staging tools for PD.

Impaired long-term memory retention: common denominator for acutely or genetically reduced hippocampal neurogenesis in adult mice.

In adult rodents, decreasing hippocampal neurogenesis experimentally using different approaches often impairs performance in hippocampus-dependent processes. Nonetheless, functional relevance of adult neurogenesis is far from being unraveled, and deficits so far described in animal models often lack reproducibility. One hypothesis is that such differences might be the consequence of the extent of the methodological specificity used to alter neurogenesis rather than the extent to which adult neurogenesis is altered. To address this, we focused on cranial irradiation, the most widely used technique to impair hippocampal neurogenesis and consequentially induce hippocampus-dependent behavioral deficits. To investigate the specificity of the technique, we thus exposed 4-5 months old female cyclin D2 knockout mice, a model lacking physiological levels of olfactory and hippocampal neurogenesis, to an X-ray dose of 10 Gy, reported to specifically affect transiently amplifying precursors. After a recovery period of 1.5 months, behavioral tests were performed and probed for locomotor activity, habituation, anxiety, and spatial learning and memory. Spatial learning in the Morris water maze was intact in all experimental groups. Although spatial memory retention assessed 24h following acquisition was also intact in all mice, irradiated wild type and cyclin D2 knockout mice displayed memory deficits one week after acquisition. In addition, we observed significant differences in tests addressing anxiety and locomotor activity dependent on the technique used to alter neurogenesis. Whereas irradiated mice were hyperactive regardless of their genotype, cyclin D2 knockout mice were hypoactive in most of the tests and displayed altered habituation. The present study emphasizes that different approaches aimed at decreasing adult hippocampal neurogenesis may result in distinct behavioral impairments related to locomotion and anxiety. In contrast, spatial long-term memory retention is consistently altered after both approaches suggesting a plausible implication of hippocampal neurogenesis in this cognitive process.

Unbiased and mobile gait analysis detects motor impairment in Parkinson's disease.

Motor impairments are the prerequisite for the diagnosis in Parkinson's disease (PD). The cardinal symptoms (bradykinesia, rigor, tremor, and postural instability) are used for disease staging and assessment of progression. They serve as primary outcome measures for clinical studies aiming at symptomatic and disease modifying interventions. One major caveat of clinical scores such as the Unified Parkinson Disease Rating Scale (UPDRS) or Hoehn&Yahr (H&Y) staging is its rater and time-of-assessment dependency. Thus, we aimed to objectively and automatically classify specific stages and motor signs in PD using a mobile, biosensor based Embedded Gait Analysis using Intelligent Technology (eGaIT). eGaIT consist of accelerometers and gyroscopes attached to shoes that record motion signals during standardized gait and leg function. From sensor signals 694 features were calculated and pattern recognition algorithms were applied to classify PD, H&Y stages, and motor signs correlating to the UPDRS-III motor score in a training cohort of 50 PD patients and 42 age matched controls. Classification results were confirmed in a second independent validation cohort (42 patients, 39 controls). eGaIT was able to successfully distinguish PD patients from controls with an overall classification rate of 81%. Classification accuracy increased with higher levels of motor impairment (91% for more severely affected patients) or more advanced stages of PD (91% for H&Y III patients compared to controls), supporting the PD-specific type of analysis by eGaIT. In addition, eGaIT was able to classify different H&Y stages, or different levels of motor impairment (UPDRS-III). In conclusion, eGaIT as an unbiased, mobile, and automated assessment tool is able to identify PD patients and characterize their motor impairment. It may serve as a complementary mean for the daily clinical workup and support therapeutic decisions throughout the course of the disease.

A progressive dopaminergic phenotype associated with neurotoxic conversion of α-synuclein in BAC-transgenic rats.

Conversion of soluble α-synuclein into insoluble and fibrillar inclusions is a hallmark of Parkinson's disease and other synucleinopathies. Accumulating evidence points towards a relationship between its generation at nerve terminals and structural synaptic pathology. Little is known about the pathogenic impact of α-synuclein conversion and deposition at nigrostriatal dopaminergic synapses in transgenic mice, mainly owing to expression limitations of the α-synuclein construct. Here, we explore whether both the rat as a model and expression of the bacterial artificial chromosome construct consisting of human full-length wild-type α-synuclein could exert dopaminergic neuropathological effects. We found that the human promoter induced a pan-neuronal expression, matching the rodent α-synuclein expression pattern, however, with prominent C-terminally truncated fragments. Ageing promoted conversion of both full-length and C-terminally truncated α-synuclein species into insolube and proteinase K-resistant fibres, with strongest accumulation in the striatum, resembling biochemical changes seen in human Parkinson's disease. Transgenic rats develop early changes in novelty-seeking, avoidance and smell before the progressive motor deficit. Importantly, the observed pathological changes were associated with severe loss of the dopaminergic integrity, thus resembling more closely the human pathology.

α-Synuclein induces alterations in adult neurogenesis in Parkinson disease models via p53-mediated repression of Notch1.

Parkinson disease is characterized by the loss of dopaminergic neurons mainly in the substantia nigra. Accumulation of α-synuclein and cell loss has been also reported in many other brain regions including the hippocampus, where it might impair adult neurogenesis, contributing to nonmotor symptoms. However, the molecular mechanisms of these alterations are still unknown. In this report we show that α-synuclein-accumulating adult rat hippocampus neural progenitors present aberrant neuronal differentiation, with reduction of Notch1 expression and downstream signaling targets. We characterized a Notch1 proximal promoter that contains p53 canonical response elements. In vivo binding of p53 represses the transcription of Notch1 in neurons. Moreover, we demonstrated that α-synuclein directly binds to the DNA at Notch1 promoter vicinity and also interacts with p53 protein, facilitating or increasing Notch1 signaling repression, which interferes with maturation and survival of neural progenitors cells. This study provides a molecular basis for α-synuclein-mediated disruption of adult neurogenesis in Parkinson disease.

Alpha-synuclein aggregation involves a bafilomycin A 1-sensitive autophagy pathway.

Synucleinopathies like Parkinson disease and dementia with Lewy bodies (DLB) are characterized by α-synuclein aggregates within neurons (Lewy bodies) and their processes (Lewy neurites). Whereas α-synuclein has been genetically linked to the disease process, the pathological relevance of α-synuclein aggregates is still debated. Impaired degradation is considered to result in aggregation of α-synuclein. In addition to the ubiquitin-proteasome degradation, the autophagy-lysosomal pathway (ALP) is involved in intracellular degradation processes for α-synuclein. Here, we asked if modulation of ALP affects α-synuclein aggregation and toxicity. We have identified an induction of the ALP markers LAMP-2A and LC3-II in human brain tissue from DLB patients, in a transgenic mouse model of synucleinopathy, and in a cell culture model for α-synuclein aggregation. ALP inhibition using bafilomycin A 1 (BafA1) significantly potentiates toxicity of aggregated α-synuclein species in transgenic mice and in cell culture. Surprisingly, increased toxicity is paralleled by reduced aggregation in both in vivo and in vitro models. The dichotomy of effects on aggregating and nonaggregating species of α-synuclein was specifically sensitive to BafA1 and could not be reproduced by other ALP inhibitors. The present study expands on the accumulating evidence regarding the function of ALP for α-synuclein degradation by isolating an aggregation specific, BafA1-sensitive, ALP-related pathway. Our data also suggest that protein aggregation may represent a detoxifying event rather than being causal for cellular toxicity.

Fluoxetine ameliorates behavioral and neuropathological deficits in a transgenic model mouse of α-synucleinopathy.

The term α-synucleinopathies refers to a group of age-related neurological disorders including Parkinson's disease (PD), Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA) that display an abnormal accumulation of alpha-synuclein (α-syn). In contrast to the neuronal α-syn accumulation observed in PD and DLB, MSA is characterized by a widespread oligodendrocytic α-syn accumulation. Transgenic mice expressing human α-syn under the oligodendrocyte-specific myelin basic protein promoter (MBP1-hαsyn tg mice) model many of the behavioral and neuropathological alterations observed in MSA. Fluoxetine, a selective serotonin reuptake inhibitor, has been shown to be protective in toxin-induced models of PD, however its effects in an in vivo transgenic model of α-synucleinopathy remain unclear. In this context, this study examined the effect of fluoxetine in the MBP1-hαsyn tg mice, a model of MSA. Fluoxetine administration ameliorated motor deficits in the MBP1-hαsyn tg mice, with a concomitant decrease in neurodegenerative pathology in the basal ganglia, neocortex and hippocampus. Fluoxetine administration also increased levels of the neurotrophic factors, GDNF (glial-derived neurotrophic factor) and BDNF (brain-derived neurotrophic factor) in the MBP1-hαsyn tg mice compared to vehicle-treated tg mice. This fluoxetine-induced increase in GDNF and BDNF protein levels was accompanied by activation of the ERK signaling pathway. The effects of fluoxetine administration on myelin and serotonin markers were also examined. Collectively these results indicate that fluoxetine may represent a novel therapeutic intervention for MSA and other neurodegenerative disorders.