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Loss of functional mitochondrial complex I (MCI) in the dopaminergic neurons of the substantia nigra is a hallmark of Parkinson’s disease 1 . Yet, whether this change contributes to Parkinson’s disease pathogenesis is unclear 2 . Here we used intersectional genetics to disrupt the function of MCI in mouse dopaminergic neurons. Disruption of MCI induced a Warburg-like shift in metabolism that enabled neuronal survival, but triggered a progressive loss of the dopaminergic phenotype that was first evident in nigrostriatal axons. This axonal deficit was accompanied by motor learning and fine motor deficits, but not by clear levodopa-responsive parkinsonism—which emerged only after the later loss of dopamine release in the substantia nigra. Thus, MCI dysfunction alone is sufficient to cause progressive, human-like parkinsonism in which the loss of nigral dopamine release makes a critical contribution to motor dysfunction, contrary to the current Parkinson’s disease paradigm 3 , 4 . Dysfunction of mitochondrial complex I in mice is sufficient to cause progressive parkinsonism in which the loss of nigral dopamine release critically contributes to motor dysfunction.

In Parkinson’s disease (PD) there is a selective degeneration of neuromelanin-containing neurons, especially substantia nigra dopaminergic neurons. In humans, neuromelanin accumulates with age, the latter being the main risk factor for PD. The contribution of neuromelanin to PD pathogenesis remains unknown because, unlike humans, common laboratory animals lack neuromelanin. Synthesis of peripheral melanins is mediated by tyrosinase, an enzyme also present at low levels in the brain. Here we report that overexpression of human tyrosinase in rat substantia nigra results in age-dependent production of human-like neuromelanin within nigral dopaminergic neurons, up to levels reached in elderly humans. In these animals, intracellular neuromelanin accumulation above a specific threshold is associated to an age-dependent PD phenotype, including hypokinesia, Lewy body-like formation and nigrostriatal neurodegeneration. Enhancing lysosomal proteostasis reduces intracellular neuromelanin and prevents neurodegeneration in tyrosinase-overexpressing animals. Our results suggest that intracellular neuromelanin levels may set the threshold for the initiation of PD. It is unclear if neuromelanin plays a role in Parkinson’s disease pathogenesis since common laboratory animals lack this pigment. Authors show here that overexpression of human tyrosinase in the substantia nigra of rats resulted in an age-dependent production of human-like neuromelanin within nigral dopaminergic neurons and is associated with a Parkinson’s disease phenotype when allowed to accumulate above a specific threshold.

Loss of dopamine in Parkinson's disease is hypothesized to impede movement by inducing hypo- and hyperactivity in striatal spiny projection neurons (SPNs) of the direct (dSPNs) and indirect (iSPNs) pathways in the basal ganglia, respectively. The opposite imbalance might underlie hyperkinetic abnormalities, such as dyskinesia caused by treatment of Parkinson’s disease with the dopamine precursor l -DOPA. Here we monitored thousands of SPNs in behaving mice, before and after dopamine depletion and during l -DOPA-induced dyskinesia. Normally, intermingled clusters of dSPNs and iSPNs coactivated before movement. Dopamine depletion unbalanced SPN activity rates and disrupted the movement-encoding iSPN clusters. Matching their clinical efficacy, l -DOPA or agonism of the D 2 dopamine receptor reversed these abnormalities more effectively than agonism of the D 1 dopamine receptor. The opposite pathophysiology arose in l -DOPA-induced dyskinesia, during which iSPNs showed hypoactivity and dSPNs showed unclustered hyperactivity. Therefore, both the spatiotemporal profiles and rates of SPN activity appear crucial to striatal function, and next-generation treatments for basal ganglia disorders should target both facets of striatal activity. In mouse models of Parkinson’s disease and dyskinesia, striatal spiny projection neurons of the direct and indirect pathways have abnormal, imbalanced levels of spontaneous and locomotor-related activity, with the two different disease states characterized by opposite abnormalities.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by degeneration of dopaminergic neurons associated with dysregulation of iron homeostasis in the brain. Ferroptosis is an iron-dependent cell death process that serves as a significant regulatory mechanism in PD. However, its underlying mechanisms are not yet fully understood. By performing RNA sequencing analysis, we found that the main iron storage protein ferritin heavy chain 1 (FTH1) is differentially expressed in the rat 6-hydroyxdopamine (6-OHDA) model of PD compared with control rats. Our present work demonstrates that FTH1 is involved in iron accumulation and the ferroptosis pathway in this model. Knockdown of FTH1 in PC-12 cells significantly inhibited cell viability and caused mitochondrial dysfunction. Moreover, FTH1 was found to be involved in ferritinophagy, a selective form of autophagy involving the degradation of ferritin by ferroptosis. Overexpression of FTH1 in PC-12 cells impaired ferritinophagy and downregulated microtubule-associated protein light chain 3 and nuclear receptor coactivator 4 expression, ultimately suppressing cell death induced by ferroptosis. Consistent with these findings, the ferritinophagy inhibitors chloroquine and bafilomycin A1 inhibited ferritin degradation and ferroptosis in 6-OHDA-treated PC-12 cells. This entire process was mediated by the cyclic regulation of FTH1 and ferritinophagy. Taken together, these results suggest that FTH1 links ferritinophagy and ferroptosis in the 6-OHDA model of PD, and provide a new perspective and potential for a pharmacological target in this disease.

Because of the highly penetrant gene mutation and clinical features consistent with idiopathic Parkinson's disease, carriers of the autosomal dominant Ala53Thr (A53T; 209G→A) point mutation in the α-synuclein (SNCA) gene are an ideal population to study the premotor phase and evolution of Parkinson's pathology. Given the known neurochemical changes in the serotonergic system and their association with symptoms of Parkinson's disease, we hypothesised that carriers of the A53T SNCA mutation might show abnormalities in the serotonergic neurotransmitter system before the diagnosis of Parkinson's disease, and that this pathology might be associated with measures of Parkinson's burden. In this cross-sectional study, we recruited carriers of the A53T SNCA mutation from specialist Movement Disorders clinics in Athens, Greece, and Salerno, Italy, and a cohort of healthy controls with no personal or family history of neurological or psychiatric disorders from London, UK (recruited via public advertisement) who were age matched to the A53T SNCA carriers. We also recruited one cohort of patients with idiopathic Parkinson's disease (cohort 1) from Movement Disorders clinics in London, UK, and retrieved data on a second cohort of such patients (cohort 2; n=40) who had been scanned with a different scanner. 7-day continuous recording of motor function was used to determine the Parkinson's disease status of the A53T carriers. To assess whether serotonergic abnormalities were present, we used [11C]DASB PET non-displaceable binding to quantify serotonin transporter density. We constructed brain topographic maps reflecting Braak stages 1–6 and used these as seed maps to calculate [11C]DASB non-displaceable binding potential in our cohort of A53T SNCA carriers. Additionally, all participants underwent a battery of clinical assessments to determine motor and non-motor symptoms and cognitive status, and [123I]FP-CIT single-photon emission CT (SPECT) to assess striatal dopamine transporter binding and MRI for volumetric analyses to assess whether pathology is associated with measures of Parkinson's disease burden. Between Sept 1, 2016, and Sept 30, 2018, we recruited 14 A53T SNCA carriers, 25 healthy controls, and 25 patients with idiopathic Parkinson's disease. Seven (50%) of 14 A53T SCNA carriers were confirmed to have motor symptoms and confirmed to have Parkinson's disease, and the absence of motor symptoms was confirmed in seven (50%) A53T SCNA carriers (ie, premotor), in whom [123I]FP-CIT SPECT confirmed the absence of striatal dopaminergic deficits. Compared with healthy controls, premotor A53T SNCA carriers showed loss of [11C]DASB non-displaceable binding potential in the ventral (p<0·0001) and dorsal (p=0·0002) raphe nuclei, caudate (p=0·00015), putamen (p=0·036), thalamus (p=0·00074), hypothalamus (p<0·0001), amygdala (p=0·0041), and brainstem (p=0·046); and in A53T SNCA carriers with Parkinson's disease this loss was extended to the hippocampus (p=0·0051), anterior (p=0·022) and posterior cingulate (p=0·036), insula (p=0·0051), frontal (p=0·0016), parietal (p=0·019), temporal (p<0·0001), and occipital (p=0·0053) cortices. A53T SNCA carriers with Parkinson's disease showed a loss of striatal [123I]FP-CIT-specific binding ratio compared with healthy controls (p<0·0001). Premotor A53T SNCA carriers had loss of [11C]DASB non-displaceable binding potential in brain areas corresponding to Braak stages 1–3, whereas [11C]DASB non-displaceable binding potential was largely preserved in areas corresponding to Braak stages 4–6. Except for one participant who was diagnosed with Parkinson's disease in the past year, all A53T SNCA carriers with Parkinson's disease had decreases in [11C]DASB non-displaceable binding potential in brain areas corresponding to Braak stages 1–6. Decreases in [11C]DASB non-displaceable binding potential in the brainstem were associated with increased Movement Disorder Score-Unified Parkinson's Disease Rating Scale total scores in all A53T SNCA carriers (r −0·66, 95% CI −0·88 to −0·20; p=0·0099), idiopathic Parkinson's disease cohort 1 (r −0·66, −0·84 to −0·36; p=0·00031), and idiopathic Parkinson's disease cohort 2 (r −0·71, −0·84 to −0·52; p<0·0001). The presence of serotonergic pathology in premotor A53T SNCA carriers preceded development of dopaminergic pathology and motor symptoms and was associated with disease burden, highlighting the potential early role of serotonergic pathology in the progression of Parkinson's disease. Our findings provide evidence that molecular imaging of serotonin transporters could be used to visualise premotor pathology of Parkinson's disease in vivo. Future work might establish whether serotonin transporter imaging is suitable as an adjunctive tool for screening and monitoring progression for individuals at risk or patients with Parkinson's disease to complement dopaminergic imaging, or as a marker of Parkinson's burden in clinical trials. Lily Safra Hope Foundation and National Institute for Health Research (NIHR) Biomedical Research Centre at King's College London.

Parkinson's disease (PD) is a common neurodegenerative disease that lacks therapies to prevent progressive neurodegeneration. Impaired energy metabolism and reduced ATP levels are common features of PD. Previous studies revealed that terazosin (TZ) enhances the activity of phosphoglycerate kinase 1 (PGK1), thereby stimulating glycolysis and increasing cellular ATP levels. Therefore, we asked whether enhancement of PGK1 activity would change the course of PD. In toxin-induced and genetic PD models in mice, rats, flies, and induced pluripotent stem cells, TZ increased brain ATP levels and slowed or prevented neuron loss. The drug increased dopamine levels and partially restored motor function. Because TZ is prescribed clinically, we also interrogated 2 distinct human databases. We found slower disease progression, decreased PD-related complications, and a reduced frequency of PD diagnoses in individuals taking TZ and related drugs. These findings suggest that enhancing PGK1 activity and increasing glycolysis may slow neurodegeneration in PD.

The pathological end-state of Parkinson disease is well described from postmortem tissue, but there remains a pressing need to define early functional changes to susceptible neurons and circuits. In particular, mechanisms underlying the vulnerability of the dopamine neurons of the substantia nigra pars compacta (SNc) and the importance of protein aggregation in driving the disease process remain to be determined. To better understand the sequence of events occurring in familial and sporadic Parkinson disease, we generated bacterial artificial chromosome transgenic mice (SNCA -OVX) that express wild-type α-synuclein from the complete human SNCA locus at disease-relevant levels and display a transgene expression profile that recapitulates that of endogenous α-synuclein. SNCA -OVX mice display age-dependent loss of nigrostriatal dopamine neurons and motor impairments characteristic of Parkinson disease. This phenotype is preceded by early deficits in dopamine release from terminals in the dorsal, but not ventral, striatum. Such neurotransmission deficits are not seen at either noradrenergic or serotoninergic terminals. Dopamine release deficits are associated with an altered distribution of vesicles in dopaminergic axons in the dorsal striatum. Aged SNCA -OVX mice exhibit reduced firing of SNc dopamine neurons in vivo measured by juxtacellular recording of neurochemically identified neurons. These progressive changes in vulnerable SNc neurons were observed independently of overt protein aggregation, suggesting neurophysiological changes precede, and are not driven by, aggregate formation. This longitudinal phenotyping strategy in SNCA -OVX mice thus provides insights into the region-specific neuronal disturbances preceding and accompanying Parkinson disease.

Mutations in glucocerebrosidase (GBA) are the most prevalent genetic risk factor for Lewy body disorders (LBD)—collectively Parkinson’s disease, Parkinson’s disease dementia and dementia with Lewy bodies. Despite this genetic association, it remains unclear how GBA mutations increase susceptibility to develop LBD. We investigated relationships between LBD-specific glucocerebrosidase deficits, GBA-related pathways, and α-synuclein levels in brain tissue from LBD and controls, with and without GBA mutations. We show that LBD is characterised by altered sphingolipid metabolism with prominent elevation of ceramide species, regardless of GBA mutations. Since extracellular vesicles (EV) could be involved in LBD pathogenesis by spreading disease-linked lipids and proteins, we investigated EV derived from post-mortem cerebrospinal fluid (CSF) and brain tissue from GBA mutation carriers and non-carriers. EV purified from LBD CSF and frontal cortex were heavily loaded with ceramides and neurodegeneration-linked proteins including alpha-synuclein and tau. Our in vitro studies demonstrate that LBD EV constitute a “pathological package” capable of inducing aggregation of wild-type alpha-synuclein, mediated through a combination of alpha-synuclein–ceramide interaction and the presence of pathological forms of alpha-synuclein. Together, our findings indicate that abnormalities in ceramide metabolism are a feature of LBD, constituting a promising source of biomarkers, and that GBA mutations likely accelerate the pathological process occurring in sporadic LBD through endolysosomal deficiency.

Wingless-type mouse mammary tumor virus (MMTV) integration site (Wnt) signaling is one of the most critical pathways in developing and adult tissues. In the brain, Wnt signaling contributes to different neurodevelopmental aspects ranging from differentiation to axonal extension, synapse formation, neurogenesis, and neuroprotection. Canonical Wnt signaling is mediated mainly by the multifunctional β-catenin protein which is a potent co-activator of transcription factors such as lymphoid enhancer factor (LEF) and T-cell factor (TCF). Accumulating evidence points to dysregulation of Wnt/β-catenin signaling in major neurodegenerative disorders. This review highlights a Wnt/β-catenin/glial connection in Parkinson’s disease (PD), the most common movement disorder characterized by the selective death of midbrain dopaminergic (mDAergic) neuronal cell bodies in the subtantia nigra pars compacta (SNpc) and gliosis. Major findings of the last decade document that Wnt/β-catenin signaling in partnership with glial cells is critically involved in each step and at every level in the regulation of nigrostriatal DAergic neuronal health, protection, and regeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD, focusing on Wnt/β-catenin signaling to boost a full neurorestorative program in PD.

Background Cognitive decline occurs frequently in Parkinson’s disease (PD), which greatly decreases the quality of life of patients. However, the mechanisms remain to be investigated. Neuroinflammation mediated by overactivated microglia is a common pathological feature in multiple neurological disorders, including PD. This study is designed to explore the role of microglia in cognitive deficits by using a rotenone-induced mouse PD model. Methods To evaluate the role of microglia in rotenone-induced cognitive deficits, PLX3397, an inhibitor of colony-stimulating factor 1 receptor, and minocycline, a widely used antibiotic, were used to deplete or inactivate microglia, respectively. Cognitive performance of mice among groups was detected by Morris water maze, objective recognition, and passive avoidance tests. Neurodegeneration, synaptic loss, α-synuclein phosphorylation, glial activation, and apoptosis were determined by immunohistochemistry and Western blot or immunofluorescence staining. The gene expression of inflammatory factors and lipid peroxidation were further explored by using RT-PCR and ELISA kits, respectively. Results Rotenone dose-dependently induced cognitive deficits in mice by showing decreased performance of rotenone-treated mice in the novel objective recognition, passive avoidance, and Morris water maze compared with that of vehicle controls. Rotenone-induced cognitive decline was associated with neurodegeneration, synaptic loss, and Ser129-phosphorylation of α-synuclein and microglial activation in the hippocampal and cortical regions of mice. A time course experiment revealed that rotenone-induced microglial activation preceded neurodegeneration. Interestingly, microglial depletion by PLX3397 or inactivation by minocycline significantly reduced neuronal damage and α-synuclein pathology as well as improved cognitive performance in rotenone-injected mice. Mechanistically, PLX3397 and minocycline attenuated rotenone-induced astroglial activation and production of cytotoxic factors in mice. Reduced lipid peroxidation was also observed in mice treated with combined PLX3397 or minocycline and rotenonee compared with rotenone alone group. Finally, microglial depletion or inactivation was found to mitigate rotenone-induced neuronal apoptosis. Conclusions Taken together, our findings suggested that microglial activation contributes to cognitive impairments in a rotenone-induced mouse PD model via neuroinflammation, oxidative stress, and apoptosis, providing novel insight into the immunopathogensis of cognitive deficits in PD.