Pathways controlling neurotoxicity and proteostasis in mitochondrial complex I deficiency.
By onNeuromuscular disorders caused by dysfunction of the mitochondrial respiratory chain are common, severe and untreatable. We recovered a number of mitochondrial genes, including electron transport chain components, in a large forward genetic screen for mutations causing age-related neurodegeneration in the context of proteostasis dysfunction. We created a model of complex I deficiency in the Drosophila retina to probe the role of protein degradation abnormalities in mitochondrial encephalomyopathies. Using our genetic model, we found that complex I deficiency regulates both the ubiquitin/proteasome and autophagy/lysosome arms of the proteostasis machinery. We further performed an in vivo kinome screen to uncover new and potentially druggable mechanisms contributing to complex I related neurodegeneration and proteostasis failure. Reduction of RIOK kinases and the innate immune signaling kinase pelle prevented neurodegeneration in complex I deficiency animals. Genetically targeting oxidative stress, but not RIOK1 or pelle knockdown, normalized proteostasis markers. Our findings outline distinct pathways controlling neurodegeneration and protein degradation in complex I deficiency and introduce an experimentally facile model in which to study these debilitating and currently treatment-refractory disorders.
Proportion and distribution of neurotransmitter-defined cell types in the ventral tegmental area and substantia nigra pars compacta
By onThis is the most complete anatomical description of transmitter-defined cell types across SNc and VTA to date. Emphasizing the heterogeneity within these dopamine-rich regions, 57% of SNc neurons express glutamate or GABA markers, as do 78% in VTA.
Dopamine across timescales and cell types: Relevance for phenotypes in Parkinson’s disease progression
By onDopamine neurons in the SNc are crucial for movement and learning. In Parkinson's Disease, their degeneration leads to various symptoms. Recent research highlights heterogeneity in these neurons, impacting PD progression and treatment development.
Alterations in neurotransmitter co-release in Parkinson’s disease
By onParkinson's disease involves degeneration of dopamine neurons, leading to basal ganglia circuit changes. These neurons also release glutamate and GABA. Understanding co-release dynamics could help identify circuit dysfunction in Parkinson's disease.
Role of dopamine neuron activity in Parkinson’s disease pathophysiology
By onNeural activity disruptions in neurodegenerative diseases like Parkinson's may occur early. Abnormal dopamine neuron activity in PD could worsen neurotoxic effects, offering insight for future treatments to protect these neurons.
The role of α-synuclein in exocytosis
By onReview focuses on α-synuclein's role in exocytosis, a key process in Parkinson's disease. Despite unclear pathogenesis, evidence points to αsyn's involvement in regulating cellular processes.
Dysfunction of Motor Cortices in Parkinson’s disease
By onIn this review, the authors discuss PD-related changes in frontal cortical motor regions, focusing on neuropathology, changes in neurotransmission, and altered network interactions.
R1441C and G2019S LRRK2 knockin mice have distinct striatal molecular, physiological, and behavioral alterations
By onLRRK2 mutations are closely associated with Parkinson’s disease (PD). Convergent evidence suggests that LRRK2 regulates striatal function. Here, by using knock-in mouse lines expressing the two most common LRRK2 pathogenic mutations—G2019S and R1441C—we investigated how LRRK2 mutations altered striatal physiology. While we found that both R1441C and G2019S mice displayed reduced nigrostriatal dopamine release, hypoexcitability in indirect-pathway striatal projection neurons, and alterations associated with an impaired striatal-dependent motor learning were observed only in the R1441C mice. We also showed that increased synaptic PKA activities in the R1441C and not G2019S mice underlie the specific alterations in motor learning deficits in the R1441C mice. In summary, our data argue that LRRK2 mutations’ impact on the striatum cannot be simply generalized. Instead, alterations in electrochemical, electrophysiological, molecular, and behavioral levels were distinct between LRRK2 mutations. Our findings offer mechanistic insights for devising and optimizing treatment strategies for PD patients.
Polygenic Parkinson’s Disease Genetic Risk Score as Risk Modifier of Parkinsonism in Gaucher Disease
By onBiallelic pathogenic variants in GBA1 are the cause of Gaucher disease (GD) type 1 (GD1), a lysosomal storage disorder resulting from deficient glucocerebrosidase. Heterozygous GBA1 variants are also a common genetic risk factor for Parkinson's disease (PD). GD manifests with considerable clinical heterogeneity and is also associated with an increased risk for PD. The objective of this study was to investigate the contribution of PD risk variants to risk for PD in patients with GD1.
Adult-Onset Deletion of ATP13A2 in Mice Induces Progressive Nigrostriatal Pathway Dopaminergic Degeneration and Lysosomal Abnormalities
By onMutations in ATP13A2 gene can cause familial Parkinson's disease. Deleting ATP13A2 in adult mice leads to dopaminergic nerve terminal loss and neuronal degeneration, mimicking symptoms of ATP13A2-related neurodegenerative diseases.
Tagless LysoIP for immunoaffinity enrichment of native lysosomes from clinical samples
By onHere, the authors report the development of the tagless LysoIP method to enable rapid enrichment of lysosomes from clinical samples and human cell lines.
Aberrant striatal firing mediates impulsive decision-making in a mouse model of Parkinson’s disease
By onNeurodegeneration in Parkinson's disease causes motor and non-motor symptoms. Dopamine therapy helps motor symptoms but can lead to impulse disorders. A mouse model showed how dopamine agonists affect striatal neurons to drive impulsive decisions.
Chronic hyperactivation of midbrain dopamine neurons causes preferential dopamine neuron degeneration
By onParkinson’s disease is linked to substantia nigra dopamine neuron death. To determine if chronic changes in activity of these neurons plays a role, the authors created a mouse model. This resulted in altered motor activity and selective neuron loss.
3D imaging of neuronal inclusions and protein aggregates in human neurodegeneration by multiscale x-ray phase-contrast tomography
By onThis study leverages X-ray phase-contrast tomography for detailed analysis of neurodegenerative diseases focusing on the 3D visualization and quantification of neuropathological features within fixed human postmortem tissue.
Cell-type-directed design of synthetic enhancers
By onWe show that deep learning models can be used to design synthetic, cell-type-specific enhancers, starting from random sequences, and that this optimization process allows detailed tracing of enhancer features at single-nucleotide resolution.
Concerning neuromodulation as treatment of neurological and neuropsychiatric disorder: Insights gained from selective targeting of the subthalamic nucleus, para-subthalamic nucleus and zona incerta in rodents
By onNeuromodulation, such as deep brain stimulation, is advancing as a clinical intervention in neurological and neuropsychiatric disorders, including Parkinson´s disease. Here, the authors review current literature in the pre-clinical research fields.
Endogenous LRRK2 and PINK1 function in a convergent neuroprotective ciliogenesis pathway in the brain
By onMutations in LRRK2 and PINK1 are linked to Parkinson’s disease. Loss of PINK1 doesn't affect LRRK2-mediated Rab phosphorylation. Both genes impair ciliogenesis through parallel pathways, suggesting a common therapeutic strategy for PD.
Molecular and spatial transcriptomic classification of midbrain dopamine neurons and their alterations in a LRRK2G2019S model of Parkinson’s disease
By onThe authors developed an optimized pipeline for single-nucleus RNA sequencing (snRNA-seq) and generated a high-resolution hierarchically organized map revealing 20 molecularly distinct DA neuron subtypes.
Remodelling of corticostriatal axonal boutons during motor learning
By onThe authors assess the activity and structural plasticity of corticostriatal axons during learning in the adult mouse brain. The structural and functional imaging show bouton reorganization to support motor skill acquisition.
Refinement of efficient encodings of movement in the dorsolateral striatum throughout learning
By onOur results show that as striatal ensembles are progressively refined, the number of active nonspecific striatal neurons decrease and the overall efficiency of the striatum information encoding for learned actions increases.
